Septins in the nervous system: from cytoskeletal dynamics to neurological disorders

Abstract

Septins are GTP-binding cytoskeletal proteins primarily known to be involved in cell division, membrane remodeling, and cytoskeletal organization. In the nervous system, septins are suggested as key regulators of neural development, including neurite outgrowth, spine morphology, and axon initial segment formation. Septins are localized to specialized membrane domains, such as dendritic spines, axon initial segments, and synaptic terminals, where they function as scaffolding components and diffusion barriers. They are abundant in neurons, oligodendrocytes, Schwann cells, and astrocytes, regulating processes like myelination and synaptic organization. In neuronal cells, specific septin isoforms such as SEPT3, SEPT5, and SEPT7 contribute to dendritic spine formation, neurotransmitter vesicle trafficking, and axonal integrity. Alterations in septin expression or assembly can disrupt synaptic architecture and neuroplasticity, emphasizing their role in neuronal homeostasis. Dysregulation of septin expression and function has been implicated in a range of neurological disorders, including demyelinating diseases like Multiple Sclerosis and Hereditary Neuralgic Amyotrophy. Abnormal septin aggregation has been observed in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Moreover, septins can modulate inflammatory responses, where antibodies for septins 5 and 7 were associated with autoimmune encephalitis conditions. This review will provide a comprehensive overview of the role of septins in the nervous system, focusing on their molecular mechanisms, cellular functions, and implications in neurological disorders.

Introduction

The cytoskeleton is a network of filamentous proteins that plays a vital role in cell morphology, movement, and division. A family of conserved proteins called septins in eukaryotes belongs to this network. They interact with actin filaments, microtubules, and the plasma membrane, greatly influencing the cell shape and cytoskeletal dynamics [1–3].

Septins are found abundantly in both the central and peripheral nervous systems. Studies have highlighted their roles in oligodendrocytes (OLs), Schwann cells (SC), and astrocytes, impacting myelination, axonal integrity, and neurotransmitter uptake [4, 5]. Different septin isoforms in multiple neuronal subtypes contribute to dendrite and axon development, synaptic structure, and axon initial segment (AIS) formation. They influence neurite growth, spine morphology, and synaptic function. They also modulate motor protein motility and vesicle trafficking in neurons [6–8].

This review paper aims to highlight the crucial role of septins in the nervous system and various neurological disorders. Understanding the involvement of septins in cellular mechanisms can offer promising insights to guide the development of novel treatment strategies aimed at mitigating the progression of neurological conditions.

Septins are the fourth cytoskeletal component

The classification of septins as the fourth cytoskeleton member emerges from their various roles in cytoskeleton-mediated processes. Contrary to actin filaments, microtubules, and intermediate filaments, septins assemble into heteromeric complexes that can polymerize not only into filaments and bundles but also higher-order structures like rings and cages, interacting with other cytoskeletal elements to control cellular processes [9]. The fundamental aspects of septin polymerization, oligomerization, and their regulation have been comprehensively detailed in several dedicated reviews, we refer readers to those works for in-depth mechanistic descriptions [3, 10–12]. Here we briefly outline these events and instead focus on their roles as the fourth cytoskeletal component, particularly in the context of cytoskeletal organization and neurodevelopment. Mammalian septins, specifically in mice and Humans, are expressed via 13 genes into various isoforms. Based on their homology domains, they are categorized into four main groups: Sept2, Sept3, Sept6, and Sept7 [13]. Here on, all septin proteins from humans are presented by SEPT, and mice/rats are presented as Sept, followed by the number.

Septins: from monomers to high-order complexes

All septins are GTP-binding proteins consisting of conserved GTP-binding domains and variable N- and C-terminal domains (Fig. 1). The GTP-binding domain consists of four motifs, G1, G2, G3, and G4, and a septin unique element, which are highly conserved. The N-terminal region is identified as a microtubule and actin-binding domain, and it contains a polybasic region to enable septin interaction with the phosphoinositide found on the plasma membrane [13, 14]. The C-terminal region or domain, on the other hand, contains a predicted coiled coil [14]

Fig. 1.

Septin family as GTPases in mammals. A Schematic structure of mammalian septins. The N-terminal region of septin, including the proline-rich domain, interacts with actin, microtubules, and septins. GTP-binding and membrane-binding domains, including polybasic domains, also interact with the plasma membrane and septins. The C-terminal region of septin is a coiled coil domain, which is necessary for septin-septin interaction, and the domain is not included in the Sept3 subgroup. B Classification of the septin family. According to previous reports, the Septin family has been classified into Sept3 subgroup, Sept2 subgroup, Sept6 subgroup, and Sept7 subgroup based on their homology domains [13]. Septins are GTPase proteins that catalyze the hydrolysis reaction from GTP to GDP, except for the Sept6 subgroup, and this reaction is responsible for septin filaments assembly and disassembly

In mammals, septins can be hetero-hexamers or hetero-octamers, acting as the septin filaments’ building block. They form through an end-to-end arrangement at two alternating binding interfaces, one between the G domains and one between the N- and C-domains. The termini of these hetero-oligomers continue to interact linearly, creating nonpolar, stable filaments. The forming filaments can assemble laterally via C-domains cross-bridge interaction, creating filament bundles, which can adopt a highly complex configuration, such as rings and cages [3, 9, 13, 15, 16].

It is known that GTP hydrolysis to GDP is one of the primary factors influencing septin dynamics and polymerization, as it induces conformational changes in the septins’ structure. However, Sept6 subgroup lacks GTPase activity. Therefore, other factors have been identified as regulators of septin dynamics in general. For example, post-translational modifications of septins and their interactions with membrane phospholipids can influence the assembly and disassembly of septin filaments and high-order structures. In particular, phosphorylation of specific domains via protein kinases can alter the septins’ GTP-binding capability and their GTPase activity. Moreover, septin polymerization can be regulated by septin interaction with other proteins, namely Borg2, Borg3, Borg5 [13, 16–18].

Septins structural cytoskeletal role

At the cellular level, septins are necessary cytoskeletal components for various structural functions. Their plasma membrane interaction can facilitate protrusion formation and ensure their proper functionality. For instance [19], demonstrated that Sept2 is critical in endothelial podosome formation, maturation, and function. SEPT2 also constitutes an important element in the cilia structure, another membranous hair-line projection. At the cilium base, SEPT2 sustains tubulin glutamylation, preventing ciliopathies like Joubert syndrome, and acts as a stabilizer of a protein complex known as the ciliopathy complex [3, 9, 20]. Further, septin can contribute to cellular motility, evidenced by infertility seen in Sept4-null mice. Sept4, among other septins, exists in the annulus region of a sperm, creating a circular propulsion force through their ring-like structure, allowing the forward motion of sperm into the female genital tract [3]. Notably, septins can also be recruited subcellularly at the organelle membrane, regulating processes such as organelle biogenesis, fusions, and fissions [20].

Septins-microtubule interaction

In addition to their structural role, a body of evidence demonstrated the modulatory role of septins in facilitating microtubules and actin functionality [20–22]. For example, septin is involved in modulating microtubule-dependent transport. It is recognized as one of the pivotal microtubule-associated proteins (MAPs) that can selectively control the motion of specific motor proteins and their respective cargos. Few studies have proven that septin directly regulates the kinesin motor protein motility [21, 23]. As an illustration, one study examined the effect of Sept9 on kinesin-1/KIF5 and kinesin-3/KIF1A. When the septin was depleted, kinesin-1/KIF5 motion was enhanced, while kinesin-3/KIF1A motion was compromised (Fig. 2). Conversely, overexpressing Sept9 contributed to the opposite effect [21]. Of note, a team of researchers conducted an in vitro experiment to analyze the physical interplay between a significant modulator of microtubule movement, the plus-end tracking end-binding protein 1 (EB1), and septin [24]. The reported equilibrium dissociation constant measurements exhibited a high bonding strength between EB1 and Sept2, Sept6, and Sept7. This indicates that septin mainly directs microtubules by communicating with EB1 proteins [24]. In neural progenitor cells of echinoderm microtubule-associated protein-like 1 (Eml1) conditional knockout mouse model, seven septins, which are Sept2, Sept3, Sept5, Sept6, Sept8, Sept9, and Sept11, were significantly downregulated. This suggests that Eml1 may have a role in septins-microtubule interaction [25].

Fig. 2.

Septin-mediated crosstalk signaling through the association between septins and microtubules. A Schematic diagram of microtubule dynamics, elongation, and bundling through the interaction between microtubules and septins. B The effect of Sept9 on kinesin-1/KIF5 and kinesin-3/KIF1A was illustrated, where overexpression of Sept9 enhances the kinesin-3/KIF1A motion while kinesin-1/KIF5 motion was inhibited

Septin-actin interaction

In addition to their microtubule interaction, septins have been shown to interact with actin filaments. This interaction can be direct, modulating the actin network structure, or indirect through actin-binding proteins, facilitating processes like compartmentalization and cell cycle [9, 12].

Although the direct role of septin in actin nucleation, branching, and dynamics is not fully understood, in vitro studies illustrated their significance in actomyosin organization and contractility [23]. Their direct association with actin filaments can facilitate the formation of rings, as well as curved and linear bundles [12, 26]. Septin-actin interaction is also essential in scaffolding proteins and establishing diffusion barriers. Septin can ensure proper protein localization, allowing effective protein–protein interaction [9]. They can restrict proteins, including those that are membrane-bound, to specific cytoplasmic and membranous regions through their communication with actin and plasma membranes. They can also direct complex structures, such as vesicles, to proper areas of the plasma membrane, aiding in endo- and exocytosis processes [9, 23].

Septin-actin indirect interaction is well recognized during the cell cycle, as it interacts with the actin-binding proteins, anillin, and non-muscle myosin II [27, 28]. Studies on yeast have illustrated the imperative contribution of septin in cellular division, particularly the cytokinesis stage. It is involved in providing the platform for the organization of the contractile ring. Notably, a study demonstrated the importance of the regulation of dynamics through modulating septin phosphorylation state as a requirement for completing the late stage of cytokinesis [29, 30]. Sept2, Sept7, Sept9, and Sept11 are the septin members identified for their role in cytokinesis. Research shows that the function of septins in cytokinesis is unrelated to contractile force generation. However, it allows the recruitment of other critical proteins to the division site [9].

Septins in cytoskeletal crosstalk

As mentioned earlier, septin can interact with actin and microtubules, regulating their functions independently. However, a new mechanism has recently been discovered that allows the growth of actin filaments to be guided by microtubules, unleashing some of the mystery behind microtubule-actin crosstalk [31]. This mechanism is critical in the formation of growth cones, specialized structures that guide neuronal development. The study provides initial evidence that septins play a role in regulating microtubule-actin interaction by directing actin filament growth. These findings indicate that the architecture of microtubules may function as a template for actin polymerization, similar to the role typically attributed to actin filaments themselves [31].

Septins in the nervous system

Septins have distinct expression profiles varied by region and cell type within the nervous system. These identified patterns support their contribution to diverse neural processes, with specific septins preferentially involved in network development and formation, axon initial segment (AIS) organization, vesicular trafficking, regulation of neurotransmitter release, and myelination. Understanding these processes will provide context for the consequences of septin disruption in later sections.

Septins expression patterns in the human brain

Transcriptomic data extracted from the Human Protein Atlas reveal several septins exhibit differential expression across human brain regions. SEPTIN2, SEPTIN4, SEPTIN7, SEPTIN8, and SEPTIN10 show the highest RNA expression in white matter and are classified in expression clusters linked with myelination or signal transduction in oligodendrocytes. SEPTIN3, SEPTIN5, SEPTIN6, and SEPTIN11 are mainly expressed in neurons, with high levels in the cerebral cortex, hippocampus, amygdala, thalamus, and pons. On the other hand, SEPTIN9 displays moderate and widespread transcript levels across the brain, peaking in the medulla oblongata, cerebellum, and cortex. Finally, the lowest RNA expression levels are expressed by SEPTIN1, SEPTIN12, and SEPTIN14 (Fig. 3). Nevertheless, their transcripts are mostly detectable in regions such as the cortex, cerebellum, and hypothalamus [32, 33]. Differential expression of septins across various regions of mouse brain was presented in [34].

Fig. 3.

Gene expression profile of septins in different regions of the human brain. A Representative image of human brain regions as seen in the Human Protein Atlas [32]. B Graph showing differential gene expression for septin isoforms in the human brain. RNA count is shown in normalized transcripts per million (nTPM). Color code for each region was displayed as a legend

Cell specific single-cell RNA-seq [35]revealed SEPTIN2 and SEPTIN7 are broadly expressed across a range of brain cell types including neurons, astrocytes, oligodendrocytes, and dendritic cells suggesting multifaceted roles in both neuronal and glial function. SEPTIN4 and SEPTIN10 were enriched in oligodendrocytes, while SEPTIN3 displays low levels in RNA profiling but exhibits synaptic localization in neurons based on imaging data [36]. Protein-level evidence [37] for SEPTIN5 indicates localization to neuropil and cerebellar Purkinje cells, with SEPTIN9 showed cytoplasmic/membranous distribution. Other septins currently lack reliable brain protein expression data and display low level cell-type specific RNA profiling. The functional roles and differential expression patterns of septins, with reference to specific cell types and developmental stages where applicable, are elaborated in the subsequent sections.

Septins play distinct spatiotemporal roles during neurodevelopment, with their expression spanning from embryonic neurogenesis to postnatal synaptic maturation. For an in-depth discussion of septin functions in brain development and post developmental neural remodeling, and neuronal morphogenesis readers are referred to the comprehensive reviews [8, 16, 38]. Essentially, at the early embryonic stages, SEPT2 is abundantly expressed in neuroblasts and neural progenitor cells, regulating the orientation of mitotic spindles and asymmetric cell division, critical for progenitor fate decisions in the ventricular zone [39]. SEPT7 localizes to intercellular bridges of dividing progenitors, interacting with KIF20A to maintain proliferative capacity [40]. During neurite formation, SEPT9 promotes asymmetric outgrowth, essential for establishing axon-dendrite polarity [41], while SEPT4/14 facilitates the transition from multipolar to bipolar morphology in migrating neurons [42]. In the postnatal brain, SEPT5, SEPT6, and SEPT7 are enriched at synapses and axon initial segments [7], contributing to synapse formation, vesicle trafficking, and spine morphogenesis by scaffolding actin and microtubule dynamics [43] and modulating HDAC6-mediated microtubule acetylation [6]. SEPT8 becomes prominent in mature neurons, supporting dendritic arborization and stabilizing myelin architecture at later stages through interactions with oligodendrocytes [44]. SEPT3 is enriched in presynaptic terminals, and upregulated during neuronal differentiation, highlighting its relevance in mature neuron functions [45]. These findings highlight the developmental stage and cell type-specific roles of septins, whose dysregulation may contribute to neurodevelopmental disorders.

Septins in glial cells

Schwann cells (SCs)

Schwann cells (SCs) are the specialized glial cells of the peripheral nervous system (PNS). Primarily, SCs are known to support the axons and ensure their myelination. However, research identified additional functions of these glial cells in the PNS. They can facilitate peripheral nerve repair and regeneration through transdifferentiation to a repair phenotype. They contribute to synapse formation and regulate synaptic transmission. They also possess immunomodulatory effects influencing innate and adaptive immunity [46, 47].

Several research findings have provided evidence supporting the presence of septins in SC. One study investigated septin expression levels in isolated sciatic nerves during the postnatal period [4]. An increase in the levels of Sept2, Sept3, Sept5, Sept6, Sept7, Sept8, Sept9, Sept10, and Sept11 was observed. Sept3, Sept8, and Sept9 demonstrated higher activity during the peak period of myelination, indicating their crucial role in PNS myelination. Contrastingly, Sept4 presented with high expression levels early on, followed by a decline as other septins were upregulated. This suggests a potential role of Sept4 in increasing SC number and division in the early stages of myelin development.

Among the discovered septins, Roth et al. [48] focused on Sept7 and found that inhibiting Sept7 in Dorsal Root Ganglion (DRG) cultures affected SC morphology and their ability to wrap around axons properly. The research also revealed an interaction between Sept7 and cytoskeleton components of SC, particularly the actin filaments. Suppression of Sept7 led to the disruption of the typical structure of actin filaments. Additionally, alterations in actin filaments affected the normal organization of Sept7, indicating a collaborative interaction between Sept7 and actin in SC, contributing to the regulation of the myelination process [48].

In a more recent study, mouse models were utilized to investigate the effects of Sept2 and Sept9 on SC myelination and their impact on the localization of other septin subunits. Suppressing Sept2 and Sept9 showed no effect on myelin biogenesis or nerve conduction velocity. However, the suppression of Sept2, and not Sept9, did affect the formation or stabilization of the septin complex in PNS myelin in vivo [49].

Astrocytes

Astrocytes contribute to neuronal activity by delivering metabolites, absorbing neurotransmitters from synapses, and buffering ion concentrations following electrical activity. They also regulate the creation of synapses throughout the central nervous system’s (CNS) development. Additionally, they can release substances in pathological conditions that control how OLs re-myelinate neural axons [46].

Growing evidence shows septins as key regulatory molecules of astrocytic functions since they are highly expressed in astrocytic processes. Kinoshita et al. [34] illustrated a similar distribution of Sept7 and Sept4 in the CNS. There was intense labeling of these two septin proteins in the molecular layer of the cerebellar cortex and the special Bergmann glia. Bergmann glial cells are special astrocytic cells found in the cerebellum, which are crucial for Purkinje cell maturation and survival. Interestingly, Sept4 and Sept7 primarily concentrate in the astrocytic processes of the neuropil and perivascular areas. While Sept7 was also found in neuronal axonal terminals, Sept4 did not exhibit synaptic localization [34]. Immunohistochemistry and mRNA-abundance profiling identified additional septins, including Sept2, Sept5, Sept8, Sept9, and Sept11, co-localization in astrocyte processes and membranes [4, 5, 46].

The involvement of septins in astrocytic physiology is further supported through their interaction with astrocytic glutamate transporters, particularly the sodium-dependent glutamate/aspartate transporter (GLAST). For the first time, Kinoshita et al. [5] showed the co-localization of Sept2 and GLAST transporters in the Bergmann glial processes in the cerebellum surrounding neuronal axons and synapses. Affinity column chromatography experiments demonstrated that Sept2 binds directly to the GLAST C-terminal in GDP-bound or nucleotide-free states. However, when Sept2 is bound to GTP, its interaction with the GLAST is compromised [5].

Although Kinoshita et al. [5] work illustrated that Sept2 doesn’t affect the expression of astrocytic GLAST transporters, it does influence the localization of the transporter. In cells transfected with Sept2-G47V, a mutant form of Sept2, with a mutation in the G1 motif hindering GTP binding, GLAST transporters were internalized, decreasing their membrane expression significantly, and their maximum glutamate uptake velocity was reduced. Further research on Bergmann glial cells demonstrated that an additional protein, CDC42 effector peri-synaptic scaffold protein, CDC42EP4, is associated with septins to mediate the interaction between GLAST and the septin complex Sept2/4/5/11(Fig. 5). Knocking out CDC42EP4 dissociated GLAST and septins, resulting in the delocalization of the GLAST transporters and loss of glutamate clearance efficacy [50]. These findings indicate that septins play a vital role in astrocytic transporter scaffolding and localization, ultimately influencing synaptic efficacy.

Fig. 5.

Septins regulate vesicular transport and neurotransmitter release at synapse

Schematic to represent septin regulation at synapse. Sept8 controls VAMP2 binding to synaptophysin, which promotes SNARE complex assembly and facilitates neurotransmitter exocytosis. Septin complex interacts with syntaxin 1 which binds to SNARE-VAMP2-SNAP2 complex [72].

In addition to proteins, emerging research also investigates ribonucleic acids, RNA, as a potential link between septins and astrocyte activity. According to Cheng et al. 2022 [51], astrocyte activation is involved in the pathophysiology of diabetic peripheral neuropathy (DPN), a common complication of diabetes. Although the underlying molecular mechanisms are poorly understood, miR-503-5p was identified as a potential modulator of astrocytic activity [52]. DPN models revealed that MiR-503-5p expression was significantly decreased in their spinal cords and astrocytes treated with high glucose, and injecting miRNA mimics markedly improved their neuropathic pain. The therapeutic effect of its mimic was partially attributed to the regulation of Sept9 expression, suggesting a possible role for septins in the pathophysiology of neuropathic pain and astrocyte activation and their therapeutic potential [52].

Oligodendrocytes (OLs)

Originating from oligodendrocyte precursor cells (OPCs), OLs are specialized glial cells that generate myelin for CNS. Unlike their PNS counterparts, these myelinating cells are unique because they can insulate several axons simultaneously. In addition to providing insulation for efficient signal transmission, OLs allocate sodium channels to the nodes of Ranvier, creating conditions suited for rapid and effective electrical conduction along neural pathways. Furthermore, OLs support axonal health by releasing lactate, which neurons use as an energy source, and neuroprotective exosomes that help neurons survive stress [53–55]. These specialized glial cells depend on a cytoskeletal framework of microtubules and F-actin to direct the extension and stabilization of their growing processes during myelination [54]. In addition to these well-characterized components, increasing evidence suggests that septins play a role in the development and maturation of OLs.

Ten septin proteins (Sept2, 3, 4, 5, 6, 7, 8, 9, 10, and 11) were detected in various OPCs and mature OLs [4, 56]. Most septins mRNAs exhibited an upregulation in myelin and lymphocyte protein (MAL)-positive cultured OLs, which were characterized as terminally differentiated OL cell lineage, compared with OPCs. Single-cell RNA sequencing data also revealed that the expression levels of Sept2, 4, 7, and 8 increased in mature OLs compared with OPCs [4, 44]. Interestingly, expressions of Sept6 and 9 mRNAs were higher in undifferentiated OPCs than in differentiated ones, suggesting that a function of these septins in the differentiation and proliferation of these cells may exist. Also, on Sept11, there was a brief increase in the intermediate CNPase-positive stage, highlighting the transition from undifferentiated OPCs to differentiating OLs, followed by a decrease during terminal differentiation. These findings propose septins and their binding partners might control key phases in OLs maturation and myelin formation [4].

These dynamic expression patterns are reflected in the cytoskeletal remodeling as OLs mature. At early stages, a rise in bundling proteins like fascin and coronins is notable with the active assembly and elongation of actin filaments. The filaments are organized into stable structures to aid membrane branching and extension. The cytoskeleton then undergoes significant remodeling at later stages of development by upregulation of proteins that facilitate membrane compaction and spreading, resulting in actin disassembly and stabilization, particularly capZ (capping), gelsolin (severing), and cofilin (filament depolymerization). Meanwhile, bundlers like anillin and ermin and crosslinkers like septins become more noticeable, strengthening the maturing myelin sheath's structural integrity [57]. Interestingly, the lack of septins during the early stages does not affect development; however, a deficiency in bundlers and crosslinkers like Sept2, 4, 7, and 8 in the mature OLs disrupts the neural circuit and results in structural irregularities of the maturing myelin sheath. This stresses the importance of distinct cytoskeletal proteins at different phases of OLs development [44, 57].

Myelin comprises distinct domains: the adaxonal membrane, paranodal loops, and juxtaparanodes. These regions rely on molecular scaffolds, including ankyrin B, protein 4.1B, and spectrin tetramers, which are cytoskeletal elements that link membrane proteins (e.g., NF155, Caspr2, contactin) with actin [58]. The septin/anillin scaffold localizes to the adaxonal (innermost) layer of the myelin sheath, stabilizing the compact myelin against lateral pressure and membrane flow. It has been shown that the myelinating OLs require two proteins, septin and anillin, to maintain their structural integrity [44]. Other than structural stabilization, specific septins were found to have specialized roles. For instance, Sept6 interacts with myelin and lymphocyte protein (MAL), a molecule involved in regulating membrane mobility and the distribution of proteolipid protein 1 (PLP1) in OLs [59]. Interestingly, Sept6-deficient mice showed normal paranodal organization and paranode-axolemma attachment in the CNS. However, Sept11 was upregulated in these mice, suggesting a compensatory relationship between Sept6 and 11 [4]. This highlights potential redundancy and plasticity within the septin family, enabling functional stability in the face of individual septin loss.

Neural progenitor regulation and brain development

Septins regulate neural progenitor cells (NPCs) in the early stages of brain development. The maintenance of the proliferative state of progenitor cells depends on the interaction of Sept7 with Kinesin family member 20 A (KIF20A) at the intercellular bridge during NPC division. Depletion of Sept7 led to premature differentiation of neuronal cells and abnormal cortical development in mice [40]. Another study on the developing zebrafish brain identified the expression of Sept10 and 12 in specific proliferative zones that contain actively dividing NPC, such as the cell linings of the ventricular system, the mid-hindbrain boundary, and the ciliary marginal zone of the eye. Additionally, there was an overlap between the Sept 10/12 expression and the proliferating cellular nuclear antigen (PCNA) marker [60]. These findings reinforce the participation of septins in early brain development.

Neuronal morphogenesis and network formation

Septins are fundamental proteins for neural network shaping, primarily in dendritogenesis and axon growth. For the first time, Radler et al. [61] demonstrated that a cytoskeletal network of Sept5/7/11 regulates neurite formation and pyramidal neuron morphology by maintaining a balance between actin filaments, filopodia, and lamellipodia. The septin complex was found to inhibit Arp2/3-mediated actin assembly, initiating pyramidal neuritogenesis. Moreover, the downregulation of Sept7 in rat hippocampus neurons resulted in aberrant soma structure and disturbed dendritic tree organization [61]. According to another study, the interaction between Sept6 and Sept7 affected axonal branching and growth in dorsal root ganglion neurons isolated from chick embryos. The research showed that overexpression of Sept6 was responsible for filopodia formation, which is an essential precursor for the formation of collateral branches; at the same time, Sept7 facilitated the invasion of the filopodia by microtubules, which prompts the maturation of these precursors into branches. The results of this study suggest that an interplay between Sept6 and 7 is needed for axonal maturation and development [40]. Consistent with the influence of Sept7 on dendritogenesis, cultured rat hippocampal neurons derived from Sept7-deficient mice demonstrated that the dendritic protrusion density increased due to overexpression, while knocking down Sept7 expression using RNA interference (RNAi) significantly reduced the protrusion density [62]. In addition, Sept3 plays a key role in synaptic activation by promoting the extension of smooth endoplasmic reticulum (sER) from the dendritic shaft into spines, a process driven by its calcium-dependent interaction with myosin-Va during long-term potentiation (LTP). Specifically, phosphorylation of Sept3 at threonine 211 enables its delocalization from the spine base and enhances its interaction with myosin-Va to regulate sER extension. This mechanism is crucial for long-term memory formation, as Sept3 deficiency leads to deficits in long-term, but not short-term, memory [63, 64]. In total, these studies presented the role of septins in regulating dendritic architecture and axonal branching, which are essential parts of neural network functioning.

Axon initial segment (AIS)

In addition to their contribution to neural network formation, septins influence the structure and function of the AIS. It has been demonstrated that the N-terminal regions of Sept5 and 6 bind Ankyrin-G (AnkG), the master organizer of the AIS that connects voltage-gated sodium channels, neurofascin186 (NF186), and β4-spectrin to form a stable signaling platform [65, 66]. This is supported by a study by Hamdan et al. [7], which identified five septin proteins, Sept3/5/6/7/11, components of the AIS proteome in NF186-BirA-expressing hippocampus neurons using the BioID proximity labeling technique. Trim46-BirA and Ndel1-BirA did not biotinylate these septins, suggesting they are specifically close to the NF186/AnkG/β4-spectrin complex (Fig. 4) instead of the distant AIS compartments. Mical3, Map6, and Klc1 were the other biotinylated proteins, further supporting compartmentalization of AIS and its functionally diverse nature [7, 67]. These findings strongly support the association between septins and AnkG, suggesting that this interaction may represent a structural and functional vulnerability for neuropathological disorders.

Fig. 4.

Possible structure and functions of septins in AIS and Node of Ranvier. A Architecture of a neuron showing the AIS location and the Ranvier node (top). Zoomed images of AIS and the node of Ranvier are shown, respectively (bottom). B Our proposed models of the AIS structure, including Sept proteins, are shown. AnkG, NF186, and septins form a complex at AIS, which is associated with AIS assembly and maintenance. Also, septins present in glial cells interact with Anillin and PI(4,5)P2 at the myelinated axon (paranode). The molecules act as a key regulator for axo-glial interactions

Neurotransmitter release and synaptic transmission

Septins regulate synaptic transmission and the release of neurotransmitters. GTPase proteins such as Sept5 and Sept9 localize near synaptic vesicles, facilitating vesicle docking and fusion. Two studies demonstrated that cyclin-dependent kinase 5 (Cdk5) phosphorylates Sept5 at serine 17 (S17) in mouse models and serine 327 (S327) in human SEPT5, implicating SEPT5 in the regulation of neurotransmitter release through its interaction with syntaxin-1 (Fig. 5). These studies found that non-phosphorylated SEPT5 was associated with increased neurotransmitter release, whereas phosphorylation reduced release efficiency [68, 69]. A more recent study examining Sept5 and Sept9 dynamics found that disruption by forchlorfenuron (FCF) treatment impairs evoked neurotransmitter release without affecting calcium influx, further supporting the role of septins in vesicle trafficking independently of calcium signaling [70]. Additionally, researchers remarked on changes in behavior and learning abilities in experiments involving Sept5-deficient (Sept5 KO) mice with different genetic profiles. However, the extent of these changes varied based on genetic background, arguing that variables other than Sept5 may influence phenotypes [71].

Presynaptic regulation has also been affected by septins. For instance, studies reported that Sept8 interacted with soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) complex proteins, such as syntaxin-1A and vesicle-associated membrane protein 2 (VAMP2) (Fig. 5).

Sept8 controls VAMP2 binding to synaptophysin, which promotes SNARE complex assembly and facilitates neurotransmitter exocytosis [72]. Additionally, Sept4 supports effective dopamine neurotransmission in presynaptic dopaminergic neurons by forming complexes with α-synuclein, the dopamine transporter (DAT), and syntaxin-1A [73]. Similarly, recent evidence indicates that Sept1 is associated with presynaptic vesicles, distributed alongside synaptophysin, a marker of presynaptic terminals, suggesting a potential role in synaptic transmission [72].

Non-phosphorylated SEPT5 was associated with increased neurotransmitter release, whereas phosphorylation by CDK5 reduced release efficiency [68, 69]. Representation of a study revealing the interaction between Sept2/4/5/11 and Glutamate transporter (GLAST) in presence of CDC42 effector and a perisynaptic scaffold protein, CDC42EP4 in astrocytes whereas CDC42EP4-/- knockout displayed disruption between the transporter and septin interaction failing to clear the neurotransmitter [50]. Septin 7 localizes at the base of dendritic spines where it contributes to postsynaptic compartmentalization and spine stability [74]. Thousand and one Amino acid kinase 2 (TAOK2)-mediated phosphorylation of SEPT7 induces the association with the scaffolding protein PSD-95.

At postsynaptic sites, Sept7 localizes to dendritic spine necks, forming a stable structure along the membrane that behaves as a selective diffusion barrier. This barrier limits the lateral mobility of membrane proteins, such as AMPA receptors, while allowing the free diffusion of cytoplasmic molecules, thereby maintaining synaptic compartmentalization and regulating receptor availability during synaptic transmission [75]. Likewise, in GABAergic synapses, Sept11 is important; downregulation of Sept11 affects dendritic spine stability and lowers the number of functional GABAergic synaptic contacts, emphasizing its essential role in maintaining inhibitory synaptic integrity [76].

Interestingly, two studies in mouse Purkinje neurons and human NPCs revealed another role for Sept7 in calcium signaling pathways [77, 78]. In Purkinje neurons, knocking out Sept7 and stromal interaction molecule 1 (STIM1) improved synaptic transmission and motor coordination, implying that downregulating Sept7 can be a compensatory mechanism when calcium homeostasis is impaired [78]. Similarly, SEPT7-deficient human neurons improved calcium entry through the Orai1 channels by enhancing STIM1-Orai1 interaction [77]. Both studies suggest that Sept7 may represent a potential therapeutic target for correcting homeostasis in states where normal calcium regulation is compromised.

Septins in neurological disorders

As explained previously, septins, in conjunction with microtubules and actin filaments, participate in various cellular processes in different nervous system cell types, including SC, astrocytes, OLs, pyramidal neurons, and dopaminergic neurons. They exhibit diverse functions, serving as scaffolds, regulators of cytoskeletal dynamics, and membrane organizers critical for neuronal structure and function. Hence, any alteration in their structure or function could lead to diseases, which could be demyelinating or neurodegenerative.

Septins in myelin-related disorders

The myelin sheath is the protective covering surrounding the CNS and PNS nerve fibers. It facilitates the rapid transmission of electrical signals along the axons. Any damage to it can block or slow down nerve impulses, leading to neurological symptoms [79]. Myelin-related disorders can be classified into two categories: demyelinating and dysmyelinating. Dysmyelinating diseases differ from demyelinating ones in that they involve axonal damage and accumulation of myelin breakdown products in addition to myelin loss [80]. These diseases can have varying degrees of severity and significantly impact an individual's quality of life.

Multiple sclerosis

Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the CNS that primarily affects young adults aged 20 to 45 years. MS is recognized to manifest in the initial and most frequent form relapsing–remitting MS (RRMS), characterized by cycles of inflammation and demyelination, followed by periods of remission [81]. In vivo and in vitro studies have elaborated on the main pathophysiological events involved in MS. They include blood–brain barrier disruption, localized immune mononuclear cells infiltration, microglia activation, OLs apoptosis, demyelination, axonal damage, and gliosis. Various genetic and environmental factors have been investigated as potential players and biomarkers in MS pathophysiology and progression [82]. So far, limited research exists on the role of septins in MS despite their localization in myelin and expression in myelinating cells.

Vastrad and Vastrad [83] performed Next Generation Sequencing (NGS) for blood samples obtained from MS patients and healthy controls identifying SEPT4 among the differentially expressed genes, downregulated in MS samples. A study investigated the link between MS and EBV and found the exact mechanism elusive but suggested molecular mimicry as a potential mechanism, where viral proteins from EBV resemble human myelin proteins and other CNS proteins, triggering an autoimmune response against myelin and CNS antigens. It has been found that serum antibodies from MS patients targeting the EBV small capsid protein BFRF3 cross-react with many types of myelin-associated septin, including SEPT9, 8, 7, 6, and 5, with SEPT9 possessing the strongest and most consistent immunoprecipitation [84].

The peripheral blood mononuclear cells are among the most critical components of MS pathophysiology, as they are key players in the inflammatory reactions taking place in the CNS. Recently, a study has successfully demonstrated the ultrastructural changes in these cells during the disease course under electron microscopy. Notably, activated mononuclear cells exhibited increased plasma membrane ruffling, abundant cytoplasm, and convoluted nuclei. They also showed an elevation in large vesicles at the plasmalemma interface and multivesicular bodies. Those vesicles released from mononuclear cells can be classified as distinct extracellular vesicles, critical players in intercellular signaling and neuroimmune crosstalk with SEPT2 being major component among the composition of the vesicles [85]. Although the exact role in MS is not fully postulated, evidence indicates SEPT2 is crucial in maintaining endothelial barrier integrity by regulating VE-cadherin organization, thus strictly controlling immune cell infiltration [86]. These findings suggest the significant impact of septin in neuroinflammation. Further research will help expand the knowledge on the role of septin in MS, positively influencing our understanding of MS pathology and management.

Hereditary neuralgic amyotrophy

The primary association between septins and human disease is hereditary neuralgic amyotrophy (HNA). HNA is a rare autosomal dominant disorder clinically characterized by acute episodes of brachial plexus neuropathy with muscle weakness and atrophy, preceded by severe pain in the shoulder and/or arm, along with weakness, sensory loss, and atrophy of the arm muscles. Although electrophysiological studies have shown focal demyelination patterns in some patients, the exact pathophysiological mechanisms involved in HNA are still under investigation [87, 88]. Nevertheless, linkage analysis studies identified an HNA-associated region mapped to the chromosome 17q25 region [89, 90].

Kuhlenbaumer et al. [91] were the first to report three mutations in the SEPT9 gene in HNA patients linked to the disease locus. The three mutations were the sequence variations 262 C → T and 278 C → T in exon two, leading to amino acid changes R88W and S93F, respectively, and the sequence variation −131G → C in the 5’ untranslated region (UTR). None of these mutations were detected in ethnically matched controls, and their sites typically exhibit high interspecies conservation. Interestingly, both mutations in exon 2 are located in a highly conserved stretch of 15 amino acids of the SEPT9 extended N terminus [91]. A recent case report identified an additional mutation, p.Arg106Trp, in the N-terminal of SEPT9 in an Indian family. This mutation resulted in a conformational change of the protein, altering the septin binding capacity to microtubules [87]. Available evidence indicates that most of the identified HNA genetic changes may impact novel repeat motifs in the N terminus spanning Amino acids 61–113, necessary in septin-septin interaction and the resulting septin microtubule binding, bundling, and neurite growth [41].

In addition to hotspots, the founder effect has been detected in European and North American families with HNA, explaining the inheritance of the disease. Specifically, they had identical intragenic duplication in exon 2 of the SEPT9 gene. These genetic duplications were also identified in patients who didn’t have the founder haplotype [92, 93], adding to the genetic heterogeneity of the disease.

Given this well-recognized genetic basis of HNA and the role of SEPT9 in functions like microtubule bundling, cytokinesis, motor trafficking, and myelination, we hypothesize the direct involvement of SEPT9 in the pathophysiology of HNA. Yet, future research is needed to understand further the exact mechanism of neuropathy in HNA and the potential of SEPT9 as a therapeutic target.

Charcot-marie-tooth disease

Charcot-Marie-Tooth disease (CMT) is primarily an inherited, chronic, progressive peripheral neuropathy. Clinically, CMT is characterized by muscle weakness, especially in the lower leg, reduced sensory perception, decreased tendon reflexes, and foot deformities. Different types of CMT exist, varying in mode of inheritance, causative genetic alteration, and phenotypic presentation. CMT neuropathy subtypes can also vary in their pathophysiology, presenting with demyelinating, axonal, or intermediate conduction velocity patterns on nerve conduction studies [94].

CMT can be due to a mutation in multiple genes such as PMP22, MPZ, GJB1, NEFL, DNM2, and MFN2. More than 80 CMT-related genes were reported, involving functions such as membrane trafficking, cytoskeletal networks, and myelination processes [95, 96].

Recently, a rare heterozygous missense variant in the SEPT9 gene was identified in a German family with a known history of CMT1 [97]. As stated, SEPT9 protein interacts with microtubules and actin, promoting asymmetric neurite outgrowth. SEPT9 is highly expressed in glial cells, including SC involved in myelination, and transgenic mouse models with CMT-related mutations have shown SC alterations [98].

The identified variant, c.1406 T > C (p.V469A), co-segregated with the CMT phenotype within the family. Hence, a mutation in SEPT9 can be considered a genetic risk factor for CMT. Although genes associated with cognitive impairment were not studied, it can be speculated that the SEPT9 mutation explains the cognitive deficit seen in the patients since not all CMT phenotypes present with cognitive changes, and other septin alterations have been linked to classical neurodegenerative disease [97]. Further clinical studies would be required to correlate SEPT9 with CMT pathogenesis better.

Leukodystrophies

Leukodystrophies represent a diverse array of genetic disorders that involve the damage of white matter in the CNS, primarily due to myelin formation or maintenance issues. Although various cellular insufficiencies drive these conditions, the exact disease mechanism of some subtypes has not been fully elucidated [78]. Nevertheless, based on possible pathological mechanisms, leukodystrophies can be classified broadly into seven main categories: hypomyelinating, demyelinating, subtypes with myelin vacuolization, astrocytopathies, leuko-axonopathies, microgliopathies, and leuko-vasculopathies [99].

Some genes have been recognized in different subtypes of leukodystrophies, such as PLP1, GJC2, AIMP1, FAM126A, POLR3B, RARS, PYCR2, and VPS11 [99]. However, limited evidence exists on the role of septins in leukodystrophies. A study published in 2019 highlighted Sept7 as one of the early dysmyelination markers in a leukodystrophy caused by plasmalogen deficiency [100]. Rhizomelic Chondrodysplasia Punctata (RCDP) is an autosomal recessive disorder caused by gene mutations in plasmalogen biosynthesis. Affected individuals usually present with congenital cataracts, shortening of proximal limbs, profound growth deficiency, epilepsy, and intellectual disability [100].

Myelin is rich in plasmalogens, a type of membrane phospholipid that forms a significant portion of the ethanolamine glycerophospholipids in myelin [101]. Using Gnpat knockout (KO) mice models, Malheiro et al. [100] confirmed that plasmalogen deficiency can impede myelin sheath formation and maintenance in the CNS by altering myelin composition, potentially triggering demyelination and the formation of vesicle-like structures due to the engulfment of axonal protrusions and resulting in worsening neurological condition. Notably, plasmalogen deficiency was linked to altered expression of myelin basic protein (MBP), Sept7, and myelin-associated glycoprotein (MAG) in the myelin, with reductions in MBP and Sept7 seen during the initial lack of myelin formation. The presence of myelin outfoldings further highlighted this low level of Sept7 [100]. The occurrence of myelin outfoldings, a common trait in various myelin diseases, has been specifically associated with the loss of cytoskeletal septin filaments in myelin [44]. Together, this could suggest the role of plasmalogen in proper septin localization.

Septins in neurodegenerative disorders

Septin disruption can impact neuronal circuits by affecting proper synaptic signaling, axonal transport, and interaction with disease-associated proteins, resulting in the progression of several neurodegenerative diseases. Beyond their role in demyelinating disorders, septin dysfunction has been implicated in diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobar Degeneration (FTLD), and Down Syndrome (DS) [12, 102]. Table 1 summarizes the list of septins and the disorders associated with them.

Table 1.

Summary of septin family members and their associated neurological disorders

Septin	Neurological Disorder	Citation
SEPT4	Multiple Sclerosis	[83]
SEPT9, 8, 7, 6, and 5		[84]
SEPT2		[85, 86]
SEPT9	Hereditary Neuralgic Amyotrophy	[87, 91–93]
SEPT9	Charcot Marie-Tooth Disease	[97]
SEPT7	Leukodystrophies	[100]
SEPT5 and 3	Alzheimer's Disease	[102, 106]
SEPT8		[105]
SEPT6 and 7		[107]
SEPT4 and 5	Parkinson's Disease	[109, 110]
SEPT14		[111]
SEPT11	Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration	[113]
SEPT4, 6, and 7	Down Syndrome	[115]
SEPT5		[116]
SEPT5	Anti-SEPT5 Autoimmune Encephalitis	[122]
SEPT7	Anti-SEPT7 Autoimmune Encephalitis	[125]
SEPT3	Anti-SEPT3 Autoimmune Cerebellar Ataxia	[126]
SEPT7	Epilepsy	[121]

Alzheimer’s disease (AD)

Alzheimer's disease (AD) is the number one cause of neurodegenerative disorder and the leading cause of dementia, characterized by progressive cognitive decline and brain atrophy. Its hallmark pathological features include neurofibrillary tangles (NFTs) and amyloid-beta (Aβ42) plaques composed of hyperphosphorylated tau protein, both of which disrupt synaptic communication and promote neuronal death [103]. Most AD cases are classified as late-onset Alzheimer's disease (LOAD), which lacks a clear inherited genetic etiology and involves complex interactions among vascular dysfunction, mitochondrial impairment, oxidative stress, impaired glucose metabolism, and neuroinflammation [104].

Within this multifactorial framework, septins emerged as essential players in AD pathogenesis. Sept5, for instance, regulates the breakdown of amyloid precursor protein (APP) in neurons. When Sept5 is silenced, APP is abnormally processed through autophagy, leading to increased production of Aβ40 and Aβ42, the primary components of amyloid plaques [102]. Sept8, a binding partner of Sept5 involved in vesicle trafficking, also modulates APP processing, further implicating septins in amyloidogenic pathways [105].

Beyond protein aggregation, septins are also linked to synaptic degeneration, a key driver of cognitive decline in AD. Györffy et al. (2020) [106] showed that synapses with impaired mitochondria produce excessive reactive oxygen species (ROS) and are tagged with complement protein C1q, marking them for removal by microglia. The research further demonstrated that Sept3 and 5 build up in these compromised synapses, correlating with C1q tagging. This suggests that septin accumulation may increase synaptic compromise, connecting these cytoskeletal proteins to intracellular dysfunction and intracellular mechanisms of synaptic loss [106].

Given their role in synaptic calcium regulation, septins are now being explored as treatment targets. A recent study identified small molecules from the ReS19-T compound family that bind to SEPT6 and 7, restoring septin filament structure and normalizing calcium entry in neurons affected by tau and Aβ toxicity. These compounds reversed synaptic dysfunction, reduced tau and amyloid pathology, and improved cognitive performance in mouse and human cell models. Notably, their effects were selective to diseased neurons, suggesting a disease-specific therapeutic window. These findings position septin-stabilizing compounds as a promising non-amyloid-based approach to AD treatment [107].

Parkinson’s disease (PD)

Parkinson's disease (PD), the second most common neurodegenerative disorder, is a progressive disease traditionally identified by its distinct range of motor (parkinsonism) and non-motor features and hallmark brain pathology involving Lewy bodies and the loss of substantia nigra neurons. Parkinsonism includes bradykinesia, rigidity, tremors, short, shuffling steps, and postural instability. Non-motor symptoms, which often appear before the onset of motor signs, include sleep disturbances (i.e., REM sleep behavior disorder), irregular bowel movements, visual hallucinations, and mood disturbances, among others. Collectively, these two domains contribute to worsening disability and the eventual loss of independence in performing basic activities of daily living [108]. Although Lewy bodies, primarily composed of alpha-synuclein, are a key pathological feature of PD, some cases lack these inclusions, indicating that alternative processes contribute to disease progression [108]. The genetic aspect of PD adds further complexity, involving numerous genes with variable penetrance and interactions between genetic and environmental factors. Among these, septins have emerged as key players.

Sept4 and five are known substrates of parkin-mediated ubiquitination. Sept4 has been demonstrated to co-accumulate with alpha-synuclein in nigral Lewy bodies of patients with PD, while Sept5 buildup is thought to contribute to disease progression. A post-mortem study of substantia nigra tissue from patients with PD revealed that Parkin mutations lead to the accumulation of SEPT5_v2, which impairs synaptic function, a pattern not seen in individuals with normal parkin function [109].

Beyond pathological observations, functional studies support the neurotoxic role of SEPT5 in dopaminergic neurons. In a dopaminergic-like cell model (PC12 cells), overexpression of SEPT5 significantly increased susceptibility to oxidative stress induced by the Parkinson ‘s-related neurotoxin salsolinol, whereas downregulating SEPT5 improved cell survival. These findings indicate that excess SEPT5, especially under parkin dysfunction, may impair vesicular trafficking and contribute to dopaminergic neuron vulnerability [110].

While some septins promote pathogenic processes, others may offer neuroprotective effects. A genetic association study in an Ashkenazi Jewish population found that specific SEPT14 variants were linked to reduced risk of PD, and SEPT14 expression was confirmed in human substantia nigra. These results suggest that different septinsmay have diverse roles, with some promoting disease susceptibility and others potentially modulating resilience [111].

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD)

The hallmark of amyotrophic lateral sclerosis (ALS) is the progressive degeneration of motor neurons, which leads to respiratory failure, dysphagia, and progressive paralysis. This degeneration frequently exhibits a spatiotemporal pattern, extending from a central nervous system focal point, suggesting that a pathogenic molecule may be transmitted from cell to cell. Protein misfolding and aggregation are central to ALS pathology. Inclusions containing TAR DNA-binding protein 43 (TDP-43), superoxide dismutase-1 (SOD1), or fused in sarcoma (FUS) are commonly observed in affected motor neurons and neighboring glial cells [112].

The combination of protein aggregation and the progressive spread of symptoms supports a prion-like mechanism of disease propagation in ALS. Interestingly, ALS shares pathophysiological features with frontotemporal degeneration with ubiquitinated inclusions (FTLD-U), particularly the accumulation of TDP-43-positive aggregates [112].

SEPT11 has been identified in FTLD-U patient brain samples enriched in detergent-insoluble fractions. SEPT11 belongs to the SEPT6 subfamily, alongside SEPT8 and SEPT10, and may contribute to forming filamentous septin complexes such as 2/6/7 and 7/9b/11. Since SEPT11 and SEPT9 share 85% sequence homology and are expressed in the CNS, their overlapping roles may suggest functional redundancy. Using targeted mass spectrometry, SEPT11 was shown to be consistently enriched approximately fourfold in FTLD-U brains compared to controls, implicating it in the pathological protein aggregation seen in neurodegenerative disease. As FTLD-U and ALS share TDP-43 pathology, identifying SEPT11 in FTLD-U inclusions further supports the potential role of septins in ALS-related neurodegeneration [113].

Down syndrome (DS)

Down syndrome (DS), or trisomy 21, is a genetic disorder due to an extra copy of chromosome 21, either in part or in its entirety. Symptoms mainly include mild to moderate intellectual disability, growth retardation, and characteristic facial features. Sept4 interacts with parkin and DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1 A), where deregulated DYRK1A is associated with DS [114]. It was shown that DYRK1A phosphorylates Sept4 at S68 and S107, which could lead to DS etiopathology [115]. Additionally, in fetuses with DS, the maldeveloped brain showed significantly reduced expression of SEPT6 and SEPT7, and SEPT4 might be hyperphosphorylated due to the overexpression of the DYRK1A kinase [16]. Given its expression in the brain and involvement in exocytosis, SEPT5 has been linked to DS. However, its role appears non-essential for normal development and function, as evidenced by the viability and normal development of Sept5 null mice. DS patients exhibit elevated mixed lineage leukemia septin-like fusion protein (MSF)-B. This finding provides a potential explanation for the increased susceptibility of children with Down syndrome to acute leukemia [116]. The available evidence is limited to the indirect association of septins with DS, although the potential involvement through multiple molecules is indicated. Further molecular studies would be required to obtain mechanistic details on the participation of SEPT4, 6, and 7 expression and phosphorylation in DS pathology.

Septins in neurodevelopmental disorders

Septins, particularly SEPT4, SEPT5, SEPT7 and SEPT11, play crucial roles in neurodevelopmental processes by regulating dendritic spine morphology, synaptic plasticity, and neuronal migration [117]. Dysregulation of SEPT7 expression and function has been implicated in autism spectrum disorders [74], and altered expression in septine 5, 6, and 11 was observed in schizoprenia and bipolar disorders [118]. Additionally, septin mutations may contribute to intellectual disability through disrupted cytoskeletal organization during critical neurodevelopmental windows [119]. Recent studies demonstrate that septin-mediated defects in neuronal polarization and axon guidance contribute to the pathogenesis of various neurodevelopmental conditions, highlighting septins as potential therapeutic targets [120]. However, as highlighted by Falk et al., [120] investigations into the role of septins in neurodevelopment are constrained by the compensatory functions of different septin isoforms. Furthermore, knockout of key septins such as Sept7 and Sept9 are embryonically lethal, thereby limiting direct insights into their specific contributions to neurodevelopment.

Septins in epilepsy

Epilepsy is a chronic disease characterized by recurrent and unprovoked seizures. The association between septins and epilepsy has not been extensively explored before. Recently, a study [121] has identified SEPT7 as a potential biomarker in epilepsy. They found that SEPT7 levels were significantly lower in children with drug-resistant epilepsy compared to those who were seizure-free with monotherapy. Furthermore, SEPT7 levels were demonstrated to be negatively correlated with drug resistance, disease, and seizure durations. This suggests that SEPT7 may contribute to abnormal dendritic structure and impaired neuronal function in chronic epilepsy. SEPT11 is enriched at post-synapse at type-II GABAergic synapses, contributing to dendritic architecture and inhibitory synaptic stability. Disruption of SEPT11 expression impairs GABAergic synaptic connectivity, potentially weakening inhibitory control and predisposing neural circuits to hyperexcitability, a hallmark of epileptogenesis [76]. While direct septin-targeting therapies are not yet available, modulating septin pathways represents a potential strategy to restore inhibitory balance and mitigate seizure activity.

Septins in autoimmune disorders

Anti-SEPT5 encephalitis is a rare autoimmune neurological condition identified by detecting SEPT5 IgG antibodies in serum or cerebrospinal fluid (CSF). Although the exact pathogenic mechanism remains unclear, evidence suggests that SEPT5 may transiently localize to the extracellular membrane during synaptic exocytosis, potentially enabling interaction with circulating antibodies [122]. Clinical presentations commonly include progressive cerebellar ataxia accompanied by prominent hyperkinetic eye movement abnormalities such as oscillopsia and vertigo. Although immunotherapies such as rituximab, plasma exchange, and bortezomib have been tried, responses are inconsistent, with some patients showing minimal improvement and others experiencing spontaneous remission [123, 124].

In contrast, SEPT7 IgG autoimmunity is more commonly associated with encephalopathy characterized by prominent neuropsychiatric features. Patients exhibit a distinct phenotype from those with SEPT5 autoimmunity, consistent with cortical rather than cerebellar involvement. SEPT7 is essential for septin complex formation and is widely distributed across the CNS, particularly at dendritic branch points and protrusions, but does not colocalize with synaptic vesicles. Overexpression of SEPT7 enhances dendritic complexity, whereas knockdown impairs dendritic and axonal growth. Reduced SEPT7 mRNA levels have also been correlated with lower spine density in the cortex of schizophrenia patients, suggesting a broader role in CNS synaptic integrity. Experimental studies support the pathogenic potential of septin autoantibodies. In vitro, IgGs purified from SEPT7 autoimmune patients inhibited neuronal spiking activity more rapidly than those from SEPT5 patients, indicating a more substantial effect on cortical circuits [125].

A recent study identified a novel septin autoantibody targeting SEPT3 as the cause of autoimmune cerebellar ataxia in three patients with a known history of malignancy. SEPT3 is highly expressed in the cerebellum, cortex, and hippocampus. In this study, the patients’ sera did not react with other septins, such as SEPT5 or SEPT7, but consistently reacted with SEPT3, confirming the antibody’s specificity. One proposed trigger for this autoimmune response is cancer immunotherapy, as two of the patients developed symptoms following treatment with interferon-alpha and nivolumab, agents known to unmask or trigger immune-related adverse events. Unfortunately, the patients with anti–SEPT3 antibodies responded poorly to immunotherapy, unlike previous reports of patients with SEPT5 or SEPT7 IgG, who demonstrated more favorable outcomes [126].

Septin-IgG autoimmunity, whether involving SEPT5, SEPT7, or SEPT3, should be considered in the differential diagnosis of autoimmune and paraneoplastic CNS disorders. The phenotypic distinctions and emerging evidence support the inclusion of septins in future diagnostic panels for seronegative or atypical autoimmune encephalitis presentations.

Conclusions

As a fourth cytoskeleton component, Septins play a significant role in the nervous system, heavily influencing the structure, function, and integrity of neurons and glial cells. Their involvement in critical processes such as neurite growth, synaptic transmission, and myelination underscores their significance in normal physiological functions and the pathogenesis of various neurological disorders. Increasing evidence supports involvement of septins in dendrite morphology, synaptic plasticity and neuronal migration, key processes in neurodevelopment. The review informs the association of septin dysregulation or function with different neurological disorders, including demyelinating, neurodegenerative, neurodevelopmental and autoimmune disorders. As the importance of septins in neuronal function and dysfunction is evident, they emerge as promising therapeutic targets. Further research must elucidate their complex interactions within the cytoskeleton and their implications in neurological diseases. In the future, the key areas to focus on would be to identify and target specific septin pathways, develop new strategies to mitigate the progression of the disorders, and improve outcomes for those with neurological impairment. In addition, new modeling techniques are essential to resolve septin-specific functions, which are currently masked by isoform co-expression. Eventually, exploring septins as critical cellular mediators contributes to the neurobiological knowledge by fostering innovative approaches in clinical practice.

Authors’ contributions

All authors contributed to the study conception and design. HH, TT and JK conceptualized the idea. RA, MA and PMB performed literature search and comprehensive analysis. RA and MA wrote the original draft, RA, MA, PMB, KA, HH, TT and JK revised the manuscript for final version.

Funding

This work was supported by Khalifa University faculty startup grant KU-FSU 8474000395.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

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Not applicable.

Competing interests

The authors declare no competing interests.