Pathological and physiological functional cross-talks of α-synuclein and tau in the central nervous system

Abstract

α-Synuclein and tau are abundant multifunctional brain proteins that are mainly expressed in the presynaptic and axonal compartments of neurons, respectively. Previous works have revealed that intracellular deposition of α-synuclein and/or tau causes many neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. Despite intense investigation, the normal physiological functions and roles of α-synuclein and tau are still unclear, owing to the fact that mice with knockout of either of these proteins do not present apparent phenotypes. Interestingly, the co-occurrence of α-synuclein and tau aggregates was found in post-mortem brains with synucleinopathies and tauopathies, some of which share similarities in clinical manifestations. Furthermore, the direct interaction of α-synuclein with tau is considered to promote the fibrillization of each of the proteins in vitro and in vivo. On the other hand, our recent findings have revealed that α-synuclein and tau are cooperatively involved in brain development in a stage-dependent manner. These findings indicate strong cross-talk between the two proteins in physiology and pathology. In this review, we provide a summary of the recent findings on the functional roles of α-synuclein and tau in the physiological conditions and pathogenesis of neurodegenerative diseases. A deep understanding of the interplay between α-synuclein and tau in physiological and pathological conditions might provide novel targets for clinical diagnosis and therapeutic strategies to treat neurodegenerative diseases.

Introduction

Neurodegenerative diseases are diagnosed on the basis of clinical symptoms in individuals mainly with progressive cognitive declines and motor impairments caused by synaptic loss and neuronal cell death. To date, Parkinson’s disease (PD) and Alzheimer’s disease (AD), the most prevalent neurodegenerative disorders, remain incurable and there are only very limited symptomatic treatments despite decades of searching for effective cures (Ke et al., 2012; Moussaud et al., 2014; Reich and Savitt, 2019; Hacker et al., 2020). PD and AD are neuropathologically defined by the presence of misfolded and aggregated α-synuclein (αSyn) and tau, respectively (Goedert et al., 1988; Spillantini et al., 1997). Both αSyn and tau are intrinsically disordered proteins abundantly expressed in the brain (Maroteaux and Scheller, 1991; Mukrasch et al., 2009), where αSyn is highly concentrated in presynaptic terminals (Maroteaux et al., 1988), whereas tau is a major neuronal microtubule-associated protein (MAP) abundantly expressed in neuronal axons (Cohen et al., 2011). Both proteins possess a propensity to organize toxic oligomers and abnormal intracellular amyloid fibrils with similar β-strand rich structures, which lead to neurodegeneration and neuronal cell death (Fitzpatrick et al., 2017; Li et al., 2018).

Increased dosage of αSyn and its N-terminal point mutations trigger the formation of abnormal protein aggregates known as Lewy bodies (LBs) and Lewy neurites (LNs), which are intimately associated with familial PD, PD with dementia, dementia with LBs (DLBs), and other related synucleinopathies (Spillantini et al., 1997; Irizarry et al., 1998; Goedert, 2001; Singleton et al., 2003). Similarly, hyperphosphorylated tau forms intracellular neurofibrillary tangles (INFs), and dominantly inherited mutations in the MAPT gene (which encodes tau protein) are believed to cause tauopathies including AD, frontotemporal dementia (FTD), progressive supranuclear palsy, frontotemporal dementia and parkinsonism linked to chromosome 17 and other tauopathies (Poorkaj et al., 1998; Lee et al., 2001; Ghetti et al., 2015). Thus, although synucleinopathies and tauopathies are generally characterized by different pathogenic proteins, they share common clinical features in cognitive/behavioral and movement disorders, strongly suggesting the existence of cross-talk between αSyn and tau in the development of neurodegenerative diseases. Indeed, co-deposition of αSyn and tau aggregates was often found in post-mortem brains, and the overlapping clinical symptoms of dementia and parkinsonism have also been reported (Robinson et al., 2018; Twohig and Nielsen, 2019; Pan et al., 2021). Accumulating evidence also shows the occurrence of molecular interactions and cross-seeding between αSyn and tau in neurodegenerative disorders (Kayed et al., 2020; Lu et al., 2020; Williams et al., 2020). Conversely, our recent study demonstrated the critical cooperation of αSyn and tau during proper corticogenesis (Wang et al., 2022). Here, we aim to summarize the functional cross-talks of αSyn and tau in physiological and pathogenic conditions.

Search Strategy

All studies cited in this review were searched on PubMed and Science Direct using the following keywords: neurodegenerative diseases, Parkinson’s disease, Alzheimer’s disease, multiple system atrophy, synucleinopathies, tauopathies, α-synuclein and/or tau, amyloid-beta, oligomerization, fibrillization, posttranslational modification, neurotoxicity and therapy. Selected references were published from 1975 to 2023. No limits were used

Physiological and Pathological Properties of α-Synuclein

αSyn, a small protein comprised of 140 amino acids (aa), was originally identified from the electric organ synapses of the Torpedo ray (Maroteaux et al., 1988). Subsequent studies revealed that αSyn is an abundant mammalian brain protein mainly expressed in presynaptic terminals, and is less abundant in muscle, red blood cells, and lymphocytes (Jakes et al., 1994; Askanas et al., 2000; Barbour et al., 2008). Under physiological conditions, αSyn is a natively unfolded protein structurally subdivided into three regions: an N-terminal amphipathic region (1–60 aa), a central hydrophobic nonamyloid-β component region (61–95 aa) and a highly acidic C-terminal region (96–140 aa) (Figure 1A; Fusco et al., 2014; Siddiqui et al., 2016). In addition, endogenous αSyn is also reported to form α-helical tetramers in cell cultures and brain tissue that are resistant to pathogenic aggregation (Bartels et al., 2011; Wang et al., 2011). In the brain, αSyn is preferentially expressed in the neocortex, hippocampus, substantia nigra, thalamus, and cerebellum, where it binds presynaptic vesicles and regulates the release and reuptake of neurotransmitters (Jao et al., 2008; Trexler and Rhoades, 2009), playing an important role in synaptic plasticity (Figure 2A; Burré et al., 2010; Kahle et al., 2000). Studies using a combination of solid-state and solution NMR spectroscopy have revealed that the N-terminal amphipathic region works as a membrane anchor, the central nonamyloid-β component region acts as a sensor of the lipid properties and the acidic C-terminal region weakly binds to the lipid membrane (Fusco et al., 2014). The release of neurotransmitters in presynaptic nerve terminals requires SNARE-complex assembly, which is promoted by αSyn via direct interaction with synaptobrevin-2/vesicle-associated membrane protein 2 (Burré et al., 2010). Both Endogenous and overexpressed αSyn bind to synaptic vesicles (SVs) and accelerates the kinetics of exocytotic events, promoting cargo discharge with dose-dependent effects on dilation of the exocytotic fusion pore in adrenal chromaffin cells (Logan et al., 2017). However, PD-linked αSyn A30P and A53T lose the effect on fusion pore dilation. Other works also reported that disruption of αSyn by a pan-synuclein antibody leads to dispersion of SVs, as well as the reduction in the reserve pool at lamprey synapse (Fouke et al., 2021), modest overexpression of αSyn markedly inhibits the exocytosis and reclustering of SVs (Nemani et al., 2010). Conversely, triple knockout mice lacking all three synuclein family members (α-, β-, and γ-synuclein) displayed more tightly clustered SVs in mice (Vargas et al., 2017), corroborating the involvement of other critical presynaptic proteins, such as synapsin and amphiphysin during SV clustering and docking (Nemani et al., 2010; Vargas et al., 2017).

Figure 1.

Structural features of αSyn and tau proteins.

(A) Schematic illustration of αSyn. αSyn is comprised of 140 aa and structurally subdivided into three regions: an N-terminal amphipathic region (1–60 aa), a central hydrophobic nonamyloid-β component (NAC) region (61–95 aa) and a highly acidic C-terminal region (96–140 aa). Seven repeats of the lipid-binding motif (XKTKEGVXXXX) consisted of 11 aa involved in the interaction with lipid membrane. PD causing point mutations is mainly located in the N-terminus, three posttranslational modification (PTM) residues located in the C-terminus. (B) Schematic illustration of tau isoforms. Tau protein is comprised of an N-terminal projection domain, a central MT-binding domain and a C-terminal tail. The alternative splicing of E2, E3 and E10 generates six human tau isoforms. According to the N-terminal inserts encoded by E2 and E3, and the C-terminal insert encoded by E10, tau isoforms can be divided in 2N4R, 1N4R, 0N4R, 2N3R, 1N3R, and 0N3R.

Figure 2.

Physiological and pathological functions of αSyn and tau in central nervous system.

(A) Physiological and pathological functions of αSyn and tau. Both αSyn and tau are neuronal microtubule-associated proteins highly expressed in presynaptic terminals and axonal compartments, respectively. While αSyn mainly involves in neurotransmitter release and reuptake, tau promotes microtubule (MT) assembly and stability in the axon. Emergence of protein oligomers or aggregates disturbs signal transduction and axonal transport regulated by αSyn and tau, producing neurotoxicity and neuronal cell damages. (B) Cooperative function of αSyn and tau during corticogenesis. In the early embryonic stage, αSyn and tau participate in neurogenesis via regulating Notch signaling and MT dynamics. αSyn and tau are tightly maintenance of neuroprogenitor pool during neurogenesis to ensure following gliogenesis in the later embryonic stage. RGC: Radial glial cell; αSyn: α-synuclein.

Although it is still under debate, previous works have reported that αSyn also plays roles in cytoskeleton dynamics. Ordonez and colleagues have demonstrated that αSyn expression promotes the reorganization of the actin filament (F-actin) network through interaction with spectrin, by which the mitochondrial fission protein Drp1 is mislocalized, leading to mitochondrial dysfunction and neuronal death in a Drosophila model of α-synucleinopathy (Ordonez et al., 2018). Cofilin 1, another actin-binding protein, promotes αSyn aggregation and transmission in vitro and in vivo, resulting in more severe neuronal degeneration and motor impairment in a mouse model of PD (Yan et al., 2022). On the other hand, αSyn also interacts with the tubulin tetramer that seems to promote microtubule (MT) nucleation and outer growth (Cartelli et al., 2016), but the MT binding region of αSyn has not been defined accurately. Several different MT binding sites of αSyn have been reported that cover the entire protein sequence, indicating that all regions of αSyn are necessary for tubulin and MT assembly (Alim et al., 2004; Zhou et al., 2010; Cartelli et al., 2016). Our previous study also demonstrated that recombinant αSyn protein promotes the formation of relatively short MTs and its stability in vitro and is further involves in the formation of short transportable MTs that are important for axonal transport (Figure 2A; Toba et al., 2017). In addition, αSyn is detected in the nucleus (Maroteaux et al., 1988; McLean et al., 2000). Nuclear αSyn has been reported to bind transcription factors to regulate protein expression (Desplats et al., 2012; Siddiqui et al., 2012); and bind double-stranded DNA to participate in DNA repair (Schaser et al., 2019).

For the past several decades, the pathological relationship between αSyn aggregation and synucleinopathies has received particular attention, especially in the pathogenesis of PD, the second most common neurodegenerative disease (Figure 2A). The soluble monomeric αSyn misfolds into insoluble aggregates and amyloid fibrils known as LBs and LNs, the major neuropathological hallmarks found in post-mortem brains with synucleinopathies (Spillantini et al., 1997; Goedert, 2001), suggesting a central role of αSyn in these disorders. A well-established pathologic trait of PD is the synaptic loss and death of nigrostriatal dopaminergic neurons triggered by misfolded αSyn aggregates, leading to characteristic disabling motor symptoms, such as resting tremor, muscular rigidity, bradykinesia and postural instability (Goedert, 2001; Maiti et al., 2017). αSyn fibrils also target other brain regions, such as the cortex and hippocampus, resulting in the impairment of synaptic transmission, neuronal cell death, and memory damage in PD patients (Diógenes et al., 2012; Durante et al., 2019).

Systematic analyses of αSyn purified from normal and diseased brains have revealed that αSyn was extensively subjected to numerous posttranslational modifications (PTMs), some of which are considered to be associated with disease progression or initiation (Anderson et al., 2006; Zhang et al., 2023). Of all PTMs, αSyn phosphorylation is the most widely studied due to its regulatory roles in oligomerization, misfolding, fibrillization, and neurotoxicity in vivo. For instance, αSyn phosphorylation at Serine-129 (S129-P) is the most prevalent PTM detected in LBs, LNs, and glial cytoplasmic inclusions of post-mortem patient brains (Fujiwara et al., 2002; Anderson et al., 2006). S129-P possesses the ability to promote the formation of αSyn oligomers and filaments in vitro (Fujiwara et al., 2002) and accelerates neuronal loss in αSyn transgenic mice (Rieker et al., 2011). However, several works have proposed disparate effects of S129-P on health. Paleologou and colleagues have reported that S129-P αSyn inhibits its fibril formation in vitro without affecting membrane-bound conformation (Paleologou et al., 2008). Consistent with this, Buck et al. have revealed that an increase in the phosphorylation level of endogenous αSyn by overexpression of polo-like kinase (PLK) 2 or PLK3 in the substantia nigra did not induce nigral dopaminergic cell death and did not show any accumulation of αSyn protein or formation of inclusions (Buck et al., 2015). Furthermore, recent work found that neuronal activity-dependent αSyn phosphorylation is S129-specific, reversible, and confers no cytotoxicity at synapsin-containing presynaptic boutons (Ramalingam et al., 2023).

Interestingly, although the level of S87-P αSyn is also increased in cell cultures and transgenic animal models of synucleinopathies, especially in patient brains with PD, AD, LB disease and multiple system atrophy, pathogenic αSyn aggregation and neurotoxicity were attenuated after phosphorylation at S87 in vitro and its mimicking phosphorylation in vivo (Paleologou et al., 2010; Oueslati et al., 2012; Zhang et al., 2023). These findings suggest that S87-P may be an attractive new drug target for the treatment of related synucleinopathies. Our recent study found a new PTM at αSyn tyrosine-126 (Y126) by tyrosine hydroxylase (TH). TH hydroxylates αSyn Y126 to Y126DOPA, and this hydroxylation promotes the formation of short fibrils/oligomers. Increasing evidence suggests that αSyn oligomers are precursors to LB pathologies and display more toxicity to affected neurons than insoluble aggregates (Bengoa-Vergniory et al., 2017). Consistently, the short fibrils/oligomers of αSyn produced higher neurotoxicity to cultured PC12 cells than the control (Jin et al., 2022). Furthermore, we detected Y126DOPA modifications in αSyn A53T transgenic mice and human brains with PD and multiple system atrophy using a specific antibody against Y126DOPA, this may be a reason why αSyn aggregation selectively attacks TH-positive dopaminergic neurons in the PD brain (Jin et al., 2022). Notably, these disease-associated PTMs of αSyn are possibly involved in its oligomerization, aggregation, and pathology spreading.

Point mutations in the N-terminus amphipathic region of the human SNCA gene (which encodes αSyn), such as A30P, E46K, A53T/E, H50Q, and G51D, have been reported to cause an autosomal dominant form of PD (Wong and Krainc, 2017). Besides, alterations in αSyn dosage by genomic duplication or triplication in the SNCA gene have been reported to cause familial PD, and the gene dosage is directly linked to disease severity and survival (Singleton et al., 2003; Chartier-Harlin et al., 2004). Mutations or multiplications in the SNCA gene accelerate αSyn fibrillization and increase its toxicity (Xu and Pu, 2016).

It has also demonstrated the potential involvement of αSyn in the pathogenesis of AD (Twohig and Nielsen, 2019). LB pathologies were found in 10–40% of AD patients who were diagnosed with memory impairments and faster cognitive declines (Olichney et al., 1998; Hyman et al., 2012; Rabinovici et al., 2016). Moreover, αSyn aggregates were also found in cytoplasmic inclusions of oligodendrocytes that cause multiple system atrophy (Gai et al., 1998; Sorrentino et al., 2018). Interestingly, the C-terminus of αSyn can directly interact with the MT-binding region of tau and inhibit the binding of tau to tubulin and MTs, resulting in increased concentrations of free tau (Jensen et al., 1999), which may be a reason why cerebrospinal fluid tau is increased in AD patients (Vergallo et al., 2018). Molecular interaction and cross-seeding were also confirmed between amyloid-beta (Aβ) and αSyn. Although, several studies reported co-deposition of αSyn and Aβ in AD patients (Jensen et al., 1995, 1997), Bachhuber and colleagues found that an interaction between αSyn and Aβ inhibits Aβ deposition and reduces plaque formation (Bachhuber et al., 2015).

Tau in Physiology and Pathology

Tau was originally identified in the porcine brain as a neuronal MAP (Weingarten et al., 1975). Similar to αSyn, tau is another intrinsically disordered protein that is preferentially expressed in neuronal axons, but is less abundant in cell bodies, nuclei, and synaptic terminals, as well as in glial cells such as astrocytes and oligodendrocytes (LoPresti et al., 1995; Merino-Serrais et al., 2013; Wang and Mandelkow, 2016). Alternative mRNA splicing occurring in exons 2, 3, and 10 of tau gives rise to six isoforms (Figure 1B), which are subdivided into four microtubule-binding repeat (4R) and 3R forms with different distribution patterns (Lee et al., 1988; Wang and Mandelkow, 2016). The insertion of repeat domain R2 encoded by exon 10 in 4R tau increased MT binding affinity with more efficient effects on promoting MT assembly than 3R tau. All of them are mainly expressed in the adult human brain, but only 3R tau is expressed in the fetal brain (Chen et al., 2010). On the other hand, in mice, only 4R tau is exclusively present in the adult brain, and 3R isoforms are predominant during the developmental stage of the embryonic brain (Lee et al., 1988; Goedert and Jakes, 1990). In the cerebral cortex of healthy adults, the amounts of 3R and 4R tau are equal (Ke et al., 2012; Niblock and Gallo, 2012), and alterations in the ratio of 3R:4R tau have been strongly implicated as a cause of neurodegeneration (Chen et al., 2010; Espíndola et al., 2018; Damianich et al., 2021). Conversely, the expression of tau in the grey matter of the neocortex is roughly two times higher than that in the white matter (Majounie et al., 2013; Mietelska-Porowska et al., 2014). Thus, accurate regulation of tau mRNA alternative splicing is critical for the maintenance of neuronal function and survival.

In the central nervous system, tau plays critical roles in regulating MT dynamics, depending on its phosphorylation state (Rodríguez-Martín et al., 2013). MT binding affinity of tau is modulated by MT affinity-regulating kinases (MAPK, PKA, or CaMKII) and protein phosphatases (PP1, PP2A, PP2B, PP2C, or PP5) (Wang and Mandelkow, 2016). The phosphorylation of tau reduces the MT binding affinity of tau and triggers the detachment of tau from MTs. tau modulates the assembly and stability of MTs by interacting with the C-terminus of tubulin. A recent cryo-EM study using a combination of single-particle analysis and Rosetta modeling has generated atomic models of tau-tubulin interaction and revealed the tau binding region in the interface between tubulin dimers (Kellogg et al., 2018). Importantly, tau is also reported to promote the assembly of labile MTs at its plus end. Axonal MTs contain stable domains towards the proximal end and labile domains towards the distal end, where tau is mainly enriched on the labile domain. In line with this, tau-depleted cultured neurons increased the stable MT mass but not the labile MTs (Tint et al., 1998; Qiang et al., 2018). Although, these findings are inconsistent with the broadly accepted idea that tau stabilizes MTs (Baas and Qiang, 2019), restoring the labile MT mass in brains with tauopathies may be an appropriate treatment. In addition, tau further participates in MT-mediated axonal transport, where tau differentially regulates motor-driven retrograde (towards the cell body driven by dynein motors) and anterograde transports (towards the axonal terminus driven by kinesin motors) (Figure 2A; Felgner et al., 1997; Dehmelt and Halpain, 2005; Kellogg et al., 2018). However, the ablation of tau did not affect axonal transport apparently, which critically depends on the stability of MTs in cultured primary neurons or in mouse optic nerve axons (Yuan et al., 2008, 2013). These results also support the notion that tau promotes labile MT assembly rather than acting as an MT stabilizer. In addition, increased MT stability in tau-depleted cell cultures may be functionally compensated by other MAPs, such as MAP1A, MAP2, and MAP6 (Harada et al., 1994; Dehmelt and Halpain, 2005; Qiang et al., 2018).

Besides its well-known roles in MT dynamics, low-level distribution of tau in synaptic terminals is considered to play important roles in cell signaling and synaptic plasticity (Ittner et al., 2010; Zhou et al., 2017). Other studies found that tau proteins are involved in the regulation of the microenvironment within neurovascular units under physiological conditions (Guo et al., 2017; Michalicova et al., 2020). Additionally, nuclear tau possesses a DNA-binding capacity that plays roles in DNA protection, integrity, and nucleocytoplasmic transport (Violet et al., 2014; Guo et al., 2017; Benhelli-Mokrani et al., 2018).

Intracellular accumulation of abnormal tau in the human brain has been implicated in many neurodegenerative diseases known as tauopathies, where hyper- and abnormally phosphorylated tau proteins are misfolded into neurofibrillary tangles (NFTs) (Figure 2A; Alonso et al., 2001; Morris et al., 2011). Neurofibrillary pathology is the hallmark of tauopathies that is propagated through connected normal cells with prion-like properties during disease progression (Mocanu et al., 2008; Ferrer et al., 2014; Kaufman et al., 2016). Previous works have revealed that mutations in the MAPT gene and hyperphosphorylation in tau proteins accelerate the formation of tau aggregates in vitro and in vivo, which affect multiple domains, including behavior, language, memory, and motor function (Alonso et al., 2001; Pan et al., 2021). Tau isoform components present in their aggregates determine different tauopathies. For example, all six tau isoforms are mixed in individuals with AD and frontotemporal dementia, and parkinsonism linked to chromosome 17. In contrast, only 4R tau isoforms are found in other tauopathies, such as argyrophilic grain disease, progressive supranuclear palsy, corticobasal degeneration, and globular glial tauopathy; whereas in Pick’s disease, only 3R tau inclusions are detected (Fitzpatrick et al., 2017; He et al., 2020; Dregni et al., 2022).

AD, the most common tauopathy, is characterized histopathologically by the deposition of Aβ in extracellular plaques and by the accumulation of tau NFTs in the neurites of neurons. Accumulated clinicopathologic evidence has revealed that the deposition of Aβ and tau is intimately correlated with neuronal loss and cognitive decline (Goedert, 2015). The exposure of neurons to Aβ oligomers also leads to tau mislocalization into the somatodendritic compartment, by which tubulin-tyrosine-ligase-like-6 is mislocalized into the dendrites, inducing spastin-mediated MT severing. This abnormal process was shown to trigger a dramatic loss of MTs, mislocalization of mitochondria, and loss of mature spines in a cellular model system of AD (Zempel and Mandelkow, 2015). Hyperphosphorylated tau, the main component of tau aggregates, reduces the ability of tau to bind MTs and promote MT assembly, resulting in an increase in non-MT-associated tau proteins in cells (Alonso et al., 1994; Wang and Mandelkow, 2016). These functionally abnormal tau proteins prefer to induce self-aggregates of paired-helical-filaments (PHFs) and straight filaments in neurons and glial cells (Feuillette et al., 2010; Ferrer et al., 2014), producing MT catastrophe in affected cells (Alonso et al., 1994). Furthermore, abnormally hyperphosphorylated tau was found to directly interact with F-actin and increase its stability in Drosophila and mouse models of tauopathy (Fulga et al., 2007). Increased stability of F-actin affected mitochondrial fission protein DRP1 distribution to mitochondria, resulting in elongated mitochondria and its dysfunction in both Drosophila and mouse neurons (DuBoff et al., 2012).

Mutations in exonic and intronic regions of the human MAPT gene cause tauopathies, including frontotemporal dementia and parkinsonism linked to chromosome 17, Pick’s disease, argyrophilic grain disease, corticobasal degeneration, and progressive supranuclear palsy (Spillantini et al., 1998; Espíndola et al., 2018). More than 80 mutations in the MAPT gene have been identified so far, emphasizing the importance of tau in neurodegeneration (Ghetti et al., 2015; Wang and Mandelkow, 2016). Similar to abnormal phosphorylation, tau mutations also display a loss of function in the affinity for MTs, and a gain of cytotoxicity owing to self-aggregation. Interestingly, some of these mutations change the relative ratio of 4R to 3R tau isoforms via varying exon 10 splicing and thus trigger tau aggregation (Hasegawa et al., 1998; Hong et al., 1998; Spillantini et al., 1998; Ghetti et al., 2015). Animal models with human tau mutations have been extensively studied as disease models (Fulga et al., 2007; Mocanu et al., 2008; Gamache et al., 2019, 2020). Genetic evidence further revealed that the MAPT gene is also one of the risk loci for PD. Several studies have confirmed MAPT involvement in cognitive impairment or dementia in PD, suggesting that the MAPT gene also participates in disease onset and contributes to the diverse clinical manifestations of PD (Pan et al., 2021).

Neuropathological Co-aggregation and Cross-Seeding

Generally, the intracellular accumulation of αSyn inclusions in the brain is the major neuropathological hallmark of PD and related synucleinopathies, while the intracellular deposition of hyperphosphorylated tau aggregates is the neuropathological trait of AD and related tauopathies. Thus, major neuropathological features are quite distinct between synucleinopathies and tauopathies. Accumulating evidence suggests that αSyn contributes to the pathophysiology of AD, and tau is also known as a risk factor and mediator in the pathogenesis of PD (Twohig and Nielsen, 2019; Pan et al., 2021). In line with this, αSyn-containing LBs were found in more than half of familial and sporadic cases of AD, and NFTs of tau were frequently observed in the autopsies of patients with PD (Ishizawa et al., 2003; Li et al., 2016). In addition, the frequent co-deposition of different disease protein aggregates was found in the same brain lesions. For example, the co-existence of pathological αSyn and tau in the same inclusions has been found in PD dementia, the LB variant of AD, and DLBs (Arima et al., 2000; Giasson et al., 2003; Ishizawa et al., 2003; Colom-Cadena et al., 2013). More importantly, accumulating clinical evidence has revealed overlap in the disease phenotypes characterized by parkinsonism and dementia (Arima et al., 2000; Ishizawa et al., 2003), suggesting remarkable cross-talks between these two proteins in the pathogenesis of multiple neurodegenerative disorders.

Both αSyn and tau are prone to misfolding into pathological fibrils and aggregates. At the molecular level, the two proteins interact with each other in vitro and in vivo. The negatively charged C-terminus of αSyn directly interacts with the MT binding region of tau that synergistically promotes the aggregation and fibrillization of each other (Jensen et al., 1999; Giasson et al., 2003; Lu et al., 2020; Yan et al., 2020; Pan et al., 2022). Emerging evidence suggests that fibrillization occurs in a nucleation-dependent manner, followed by seed-dependent propagation (Nonaka et al., 2010). The injection of pathological conformers of αSyn or tau into healthy tissue has been shown to cross-seed each aggregation in animal models (Clavaguera et al., 2009; Guo and Lee, 2014). A recent study demonstrated that intracerebral injection of tau strains extracted from different tauopathy brains into 6hTau mice expressing the equal ratio of human 3R and 4R tau isoforms induced cell-type specific tau pathologies composed of the same isoform (He et al., 2020). Most notably, prion-like propagation of disease proteins was confirmed in several human PD patients in whom the striatum was implanted with fetal human midbrain neurons. LB-like inclusions were found in grafted nigral neurons 11–16 years after transplantation, suggesting that pathogenic proteins can propagate from the host to transplanted cells (Kordower et al., 2008; Li et al., 2008).

The conversion of soluble αSyn and tau into insoluble amyloid-like fibrils and aggregates is the central event in the development of neurodegeneration. Mutations in the SNCA or MAPT gene promote protein aggregation and disease progression. Interestingly, distinct αSyn strains displayed different efficiencies in cross-seeding tau aggregation in neuronal cells and in human P301S tau transgenic mice (Guo et al., 2013). Previous works also revealed that the overexpression of αSyn in oligodendroglial cells promotes tau aggregation (Riedel et al., 2009), and a familial PD mutation, A53T αSyn, causes the ectopic localization of tau to postsynaptic spines, culminating in postsynaptic deficits (Singh et al., 2019). This tau-mediated synaptic dysfunction was considered to contribute to hippocampal network hyperexcitability and exacerbate cognitive dysfunction in a PD mouse model (Singh et al., 2019). In addition, Teravskis and colleagues revealed that human A53T αSyn, but not A30P or E46K mutations, induces GSK3β-dependent tau phosphorylation and calcineurin-dependent loss of postsynaptic surface AMPA receptors, which leads to tau missorting to dendritic spines and postsynaptic dysfunction in A53T αSyn transgenic mice (Teravskis et al., 2018). Given the importance of tau in the development of dementia, tau abnormalities occurring in A53T αSyn transgenic mice may contribute to dementia (Irwin et al., 2017; Teravskis et al., 2018). Similarly, the overexpression of tau promotes the aggregation of αSyn and increases its size in neuronal cell models, exacerbating cytotoxicity (Badiola et al., 2011). Furthermore, tau-modified αSyn fibrils enhanced seeding activity and displayed more severe motor symptoms and cognitive dysfunction in mice (Pan et al., 2022).

Studies combining clinical diagnosis with autopsy have also found that Lewy-related pathology and AD neuropathology occur in healthy elderly individuals who do not develop parkinsonism and/or dementia during their lifetime (Knopman et al., 2003; Markesbery et al., 2009; Kok et al., 2022). For instance, around 24% of the autopsied healthy control cases exhibited Lewy-related pathology, and 20–40% of the cognitively normal older individuals exhibited AD pathology (Knopman et al., 2003; Markesbery et al., 2009). These findings have led to the speculation that some individuals are more resistant to the disease pathology, and some individuals are in a presymptomatic disease stage. Of note, mutations occurring in the PRKN gene (which encodes parkin protein) or LRRK2 gene (which encodes LRRK2 protein) also elicit neuronal degeneration without αSyn-related pathologies or tau inclusions (Gaig et al., 2009; Calogero et al., 2019). Other works have also suggested that dysfunction in autophagy, a protein degradation system, is implicated in neurodegeneration (Fîlfan et al., 2017). These works support the notion that abnormal protein inclusions in the central nervous system may work as protective events (Markesbery et al., 2009; Kok et al., 2022). In addition, aging itself is the strongest risk factor for neurodegeneration. Taken together, these findings support the notion that the soluble oligomeric forms of αSyn and tau, but not insoluble fibrils or aggregates are the main culprits for neurodegeneration (Bengoa-Vergniory et al., 2017).

Cooperative Functions of α-Synuclein and tau during Brain Development

Owing to their disease relevance, αSyn and tau have received particular attention in the physiological functions and pathogenic mechanisms of neurodegenerative diseases. Unfortunately, their physiological functions remain largely elusive, as mice with complete deletion of either of these proteins do not present overt phenotypes (Harada et al., 1994; Abeliovich et al., 2000; Ke et al., 2012). Both αSyn and tau are known to promote MT assembly and stability in vitro (Cleveland et al., 1977; Toba et al., 2017). These works strongly indicate that some functional redundancy may exist among neuronal MT-binding proteins (Harada et al., 1994; Qiang et al., 2018).

Neuronal MTs are essential for cell morphology, neurodevelopment, and maintenance of physiological functions, especially axonal transport (Sleigh et al., 2019). Hence, mutations in tubulins or neuronal MT-binding proteins have been implicated in the induction of many neurodevelopmental (Fallet-Bianco et al., 2008; Jin et al., 2017) and neurodegenerative diseases (Calogero et al., 2019; Shafiq et al., 2021). The interaction of αSyn with tau disturbs the tau-tubulin interaction and promotes tau hyperphosphorylation, resulting in MT disorganization and tau aggregation (Jensen et al., 1999; Moussaud et al., 2014).

Our recent work has shown that αSyn^–/–tau^–/– mice presented smaller brains in adulthood, but displayed a large brain in size during the embryonic stage (Wang et al., 2022). We also found that loss of αSyn and tau functions caused a reduction in Notch signaling, resulting in accelerated neurogenesis at the early embryonic stage. In utero experiments during the embryonic day (E) 12–E14 confirmed accelerated interkinetic nuclear migration in the ventricular zone and overproduction of early-born neurons in the neocortex. Consequently, overconsumption of progenitor cells occurred in the early embryonic stage, by which neural progenitor cells were quickly decreased at the middle stage, this ultimately affected gliogenesis (oligodendrogenesis and astrogenesis) at the later stage of corticogenesis (Figure 2B). The ablation of αSyn and tau further suppressed the expansion and maturation of macroglial cells (oligodendrocytes and astrocytes) concomitant with increased neuronal cell density in the postnatal brain, which in turn reduced the brain size and cortical thickness compared with the control. Thus, our study revealed the functional cooperation of αSyn and tau during corticogenesis (Wang et al., 2022). The underlying mechanisms by which αSyn and tau cooperatively regulate Notch signaling pathway and microtubule dynamics need to be elucidated with additional studies in the near future.

Implications for Therapy

Understanding the molecular pathogenesis of neurodegenerative diseases including PD and AD provides new opportunities for the development of effective therapies. The pathological interaction of αSyn and tau has been implicated in promoting their fibrillization and cross-seeding (Jensen et al., 1999). In addition, studies using transgenic mice overexpressing wild-type or familial PD mutations of αSyn led to tau hyperphosphorylation and misfolding resembling NFTs that were found in patient brains (Jensen et al., 1999). It is reasonable to assume that there is a drug that can prevent abnormal interactions between αSyn and tau, may disturb or halt the initiation of fibrillization and cross-seeding. However, our recent study revealed that αSyn and tau cooperatively execute critical roles during corticogenesis, and the loss of their physiological functions destroyed the balance between neuronal cells and glial cells (Wang et al., 2022). Both αSyn and tau interact with tubulin and promote MT assembly, suggesting that developmental abnormalities are attributed to disturbed MT dynamics. Although further study is needed to clarify the precise mechanisms underlying the cooperative functions of αSyn and tau during brain development, our findings may provide new mechanistic insights and expand the therapeutic opportunities for neurodegenerative diseases.

Transcellular propagation of protein pathogens in a prion-like manner is widely accepted as a necessary event in the pathogenesis and progression of neurodegenerative diseases (Goedert, 2015, 2017). An expanding number of studies focusing on the oligomeric forms of pathogenic proteins have reported that early-formed soluble protein oligomers are the pathogenic and neurotoxic species that lead to disease initiation and propagation rather than the insoluble forms of fibril aggregates (Paleologou et al., 2009; Sengupta et al., 2015). Furthermore, elevated amounts of soluble oligomers are linked to disease severity and are considered the culprits that cause neuronal damage and degeneration (Nonaka et al., 2010). The inhibition of soluble oligomer release or reuptake might be a therapeutic target.

Based on the neurotoxicity from soluble oligomers or protofibrils, an effective approach might be developed to remove them from the patient brain. Although there remain many challenges, immunotherapy research has made many achievements in AD treatment. After some failures in clinical trials, such as those of bapineuzumab, solanezumab, and crenezumab (Salloway et al., 2014; Cummings et al., 2018; Honig et al., 2018), some monoclonal antibodies are now making it through to the late phase of clinical development. Aducanumab, with the brand name of Aduhelm, is an anti-human Aβ antibody that targets its aggregated forms and binds to amino acids 3–7 of the Aβ peptide (Sevigny et al., 2016); lecanemab, sold under the brand name of Leqembi, is a humanized version of the mouse mAb158 monoclonal antibody targeting soluble Aβ oligomers with high affinity for which positive data have been shown in clinical trials (Magnusson et al., 2013). In addition, aducanumab was approved by the U.S. Food and Drug Administration (FDA) in 2021, and lecanemab was recently approved by the FDA in January 2023. In addition to aducanumab and lecanemab, some other monoclonal antibodies, such as donanemab, are currently waiting for approval (Mintun et al., 2021; Rashad et al., 2022). Thus, immunotherapy might be one of the most topical ways to threat AD over a period of time.

On the other hand, until now, there have been no positive data shown in monoclonal antibody therapy for PD treatment through clinical trials (Saeed et al., 2020). For PD patients, medication is still the most commonly used treatment. Although first-line drugs such as levodopa can significantly improve the cardinal motor symptoms of PD, patients who are medication refractory might also need other alternative methods. Since the mid-1990s, a kind of invasive surgical method, deep brain stimulation, has been used for pharmacologically resistant patients (Limousin et al., 1995; Hacker et al., 2020) and can improve motor symptoms and the medication-related side effects of chronic dopamine replacement (Benabid et al., 1996; Weaver et al., 2009). Over the years, technical advances in deep brain stimulation have led to the adaptability, reversibility and feasibility of performing bilateral intervention, but high-risk complications, some specific contraindications of patients (such as elderly age and psychiatric disorders), surgical team experience and economic aspects have limited this implementation (Neumann et al., 2023). In addition, a noninvasive approach called magnetic resonance-guided focused ultrasound allows effective improvement of the cardinal motor features of PD patients with an acceptable profile of side effects (Martínez-Fernández et al., 2018). An approved neurosurgery by the FDA is Exablate Neuro, which uses a focused ultrasound device to target specific areas deep in the brain, so that the beams can disrupt targeted brain tissue to treat motor symptoms (Wang et al., 2022).

The high-resolution structures using electron cryo-microscopy and solid-state NMR spectroscopy have revealed that one pathogenic protein has the ability to form amyloid fibrils with different structures (different conformational strains) that is known as polymorphism. Studies using tau fibrils extracted from the brains of individuals with AD (Fitzpatrick et al., 2017; Falcon et al., 2018; Shi et al., 2021), and αSyn filaments derived from individuals with multiple system atrophy or DLB showed high structural polymorphisms (Schweighauser et al., 2020), suggesting that different conformational strains of amyloid fibrils induce different types of neurodegenerative disease (Li and Liu, 2022). These structural insights of pathogenic amyloid fibrils may provide diagnostic and potential therapeutic relevance, and help researchers perform structure-based development of drugs that prevent fibril formation.

Funding Statement

Funding: This work was supported by the Natural Science Foundation of Guangxi Zhuang Autonomous Region, Nos. 2022GXNSFAA035622 (to MJ), 2020GXNSFAA297048 (to ZZ); the National Natural Science Foundation of China, No. 82060268 (to ZZ).