Polyamine Metabolism in Brain Health and Disease

Abstract

Polyamines, primarily spermidine and spermine, are small polycationic molecules essential for cell growth, signaling, and survival. Through electrostatic interactions with nucleic acids, lipids, and proteins, they regulate gene expression, organelle function, and adaptive responses to environmental cues. Polyamine metabolism also intersects with a myriad of other cellular pathways, including methionine, acetyl-CoA, and oxidative stress pathways, and is therefore involved in epigenetic control, cellular metabolism, and stress-response regulation. In the brain, beyond these general cellular functions, polyamines act as dynamic modulators of neurodevelopment, neural maintenance, and synaptic plasticity by influencing local proteostasis, transmitter release, and ion channel activity in both neurons and glia. Emerging evidence indicates that disruption of polyamine homeostasis contributes to neurological disorders as diverse as rare inborn errors of metabolism and common neurodegenerative diseases. Mutations in polyamine metabolic or transport genes lead to syndromes characterized by intellectual disability, hypotonia, movement disorders, and neurodegeneration; therefore, polyamine balance is critical for brain development and maintenance. In conditions such as Alzheimer’s and Parkinson’s diseases, dysregulated polyamine synthesis, catabolism, or lysosomal transport perturbs autophagic flux and proteostasis, thereby promoting Tau and α-synuclein aggregation, oxidative stress, and neuronal loss. Multi-omics analyses have further revealed that polyamine metabolism shapes glial inflammatory responses. Therapeutically, modulation of polyamine metabolism offers multiple intervention points. Spermidine supplementation or administration of polyamine analogues has been found to enhance autophagy and improve cognitive performance in models of aging and Alzheimer’s disease. Additional strategies to reestablish metabolic equilibrium and support neuronal resilience include targeted manipulation of key enzymes, such as ornithine decarboxylase 1 (ODC1), spermidine/spermine acetyltransferase 1 (SAT1), spermine oxidase (SMOX), and spermine synthase (SMS), or restoration of lysosomal polyamine export via ATP13A2. This review synthesizes current understanding of polyamine metabolism in brain health and disease, by integrating molecular, cellular, and systems-level perspectives, and further highlights emerging therapeutic directions aimed at harnessing this pathway to mitigate neurological pathology.

1. INTRODUCTION

Polyamines, primarily spermidine and spermine, and their precursor putrescine, are ancient and ubiquitous regulators of cellular physiology. Derived from amino acid precursors such as ornithine and methionine, these molecules are present in virtually all living organisms, including bacteria and mammals, thus underscoring their evolutionary importance [1,2]. Given their polycationic nature, polyamines readily interact with negatively charged cellular molecules including DNA, RNA, phospholipids, and acidic proteins. Through these interactions, polyamines influence chromatin structure and nucleic acid conformation, and modulate the activity of ion channels and enzymes [3–7]. Consequently, polyamines exert broad regulatory control over gene expression, cell signaling, and metabolic adaptation.

Because polyamines have central roles in cellular function, their metabolism is tightly regulated at the transcriptional, translational, and post-translational levels [8–12]. These regulatory mechanisms are particularly crucial in the central nervous system, because neurons and glia have limited regeneration ability and must maintain polyamine levels within narrow physiological limits, as supported by the observation that genetic manipulation of enzymes involved in polyamine metabolism typically results in only modest changes in brain polyamine levels yet leads to substantial neurological dysfunction [13–15]. Notably, physiological polyamine concentrations in the brain vary by species, developmental stage, brain region, and cell type; consequently, rigorously matched controls are essential in assessing disease-associated changes [16–18]. Disturbances in polyamine synthesis, catabolism, or transport can have wide-ranging pathological consequences (Fig 1). Altered expression or activity of key metabolic enzymes, including ornithine decarboxylase 1 (ODC1), spermine synthase (SMS), spermine oxidase (SMOX), and spermidine/spermine acetyltransferase 1 (SAT1), or major transporters, including ATP13A2 and ATP13A3, has been associated with diverse neurological conditions, such as neurodevelopmental syndromes including Buchman-Bupp syndrome (BABS) and Snyder-Robinson syndrome (SRS), as well as neurodegenerative diseases including Kufor-Rakeb syndrome, Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and ataxia [13,14,19–26].

Figure 1 ∣.

Polyamine synthesis, catabolism, and transport in eukaryotic cells. Mutations in the transporter ATP13A2, and the enzymes ODC1 and SMS cause Kufor-Rakeb syndrome (KRS), BABS (Buchman-Bupp syndrome), and SRS (Snyder-Robinson syndrome), respectively. The transporter responsible for exporting polyamines from cells has not yet been identified (indicated by a question mark). The diagram was created with BioRender.

This review synthesizes current understanding of how polyamine homeostasis influences brain development, function, and pathology, and highlights emerging therapeutic perspectives that target polyamine metabolism to preserve brain health. Sources were selected from PubMed and Web of Science, with a specific focus on studies examining polyamines in the brain.

2. OVERVIEW OF POLYAMINE METABOLISM

Polyamine metabolism is highly conserved and intricately regulated. The biosynthetic pathway begins with the decarboxylation of ornithine to putrescine, the simplest diamine, in a reaction catalyzed by ODC1. This critical rate-limiting enzyme undergoes rapid turnover via proteasomal degradation mediated by the regulatory protein antizyme, thereby enabling tight temporal control of polyamine synthesis [11,27]. From putrescine, successive additions of aminopropyl groups lead to the formation of spermidine and spermine, catalyzed by spermidine synthase (SRM) and SMS, respectively. These reactions use the aminopropyl donor decarboxylated S-adenosylmethionine (dcSAM), generated by S-adenosylmethionine decarboxylase (AMD1) [28,29]. The interconnections between polyamine and methionine metabolism position the pathway as a critical node linking methylation ability, cellular growth, and metabolic homeostasis (Fig 1).

Polyamine catabolism is equally essential in maintaining intracellular polyamine balance. Degradation occurs primarily through acetylation and oxidative deamination reactions that either recycle or eliminate excess polyamines. SAT1 catalyzes the acetylation of spermidine and spermine, by using acetyl-CoA as the acetyl group donor, and produces acetylated derivatives that serve as substrates for polyamine oxidase (PAOX) enzymes or are exported from cells [30,31]. Oxidative catabolism by PAOX converts higher polyamines back to putrescine or spermidine, while generating byproducts such as hydrogen peroxide and 3-acetylaminopropanal [32]. Spermine is also directly oxidized by SMOX and converted back to spermidine, while generating the byproducts hydrogen peroxide and 3-aminopropanal [33]. These oxidation products act as signaling intermediates that modulate cellular stress responses, apoptosis, and inflammation, but they can potentially contribute to oxidative stress if they are not properly detoxified [22,34]. Therefore, polyamine catabolism not only balances biosynthetic flux but also integrates redox and stress pathways that are particularly critical in the nervous system.

Polyamine homeostasis is further controlled by intracellular or extracellular transport. Polyamines are taken up from the gut or from extracellular environments by specific membrane transporters, then redistributed into cellular organelles or the cytosol. ATP13A2 and ATP13A3, members of the P5-type ATPase family, have recently been identified as key transporters mediating lysosomal polyamine import and export [23,35,36]. These transporters are particularly relevant in neuronal and glial cells, in which ATP13A2 defects are associated with neurodegenerative phenotypes resembling Parkinson’s disease. In addition, the solute carrier SLC45A4 has been implicated in proton-coupled polyamine transport at the plasma membrane, thus expanding the understanding of polyamine uptake mechanisms [37]. Although several candidate proteins have been proposed, the specific transporters responsible for cellular polyamine export remain incompletely defined. Therefore, multiple pathways involving vesicular secretion or exocytosis, potentially with cell type specificity, might exist. The bidirectional transport of polyamines enables local concentration control within tissues and contributes to intercellular signaling, particularly in the brain’s extracellular milieu.

Stringent regulation of polyamine metabolism occurs at multiple levels. Feedback regulation by antizymes and antizyme inhibitors provides a rapid and reversible system for modulating ODC1 activity in response to intracellular polyamine levels [11,27,38]. When polyamine concentrations rise, induction of antizyme expression leads to ODC1 degradation and decreased synthesis; in contrast, antizyme inhibitors restore ODC1 activity under conditions of depletion. In parallel, the activity of SAT1 and SMOX is highly inducible by stimuli such as oxidative stress, cytokine signaling, or hormonal changes, thereby allowing cells to dynamically adjust polyamine flux in response to metabolic or environmental cues [39–43]. Perturbation at any point in the biosynthetic, catabolic, or transport pathways can substantially disrupt cellular homeostasis and viability. Understanding the coordination among these pathways provides critical insights into how polyamine metabolism contributes to both cellular function and pathology.

A key challenge in understanding pathogenesis is disentangling the effects of altered polyamine levels from those of disrupted polyamine metabolic processes. As noted above, polyamine synthesis consumes SAM-derived dcSAM, whereas polyamine catabolism consumes acetyl-CoA, and generates hydrogen peroxide and aldehydes (Fig 1). These substrates and byproducts participate broadly in various other essential cellular activities, including protein and nucleic acid modification, energy metabolism, cell signaling, and stress responses [44–46]. Therefore, perturbation of polyamine metabolism affects not only polyamine abundance but also the levels of these associated metabolites. These functions provide an alternative explanation for the observation that genetically manipulated brains exhibit only modest changes in total polyamine levels despite pronounced neurological dysfunction. Moreover, the local concentrations of polyamines within specific cellular compartments are critical for regulating spatially restricted cellular processes and might not be accurately reflected by bulk cellular measurements [23]. Determining the relative contributions of changes in total versus local polyamine concentrations, as well as alterations in the metabolic pools of substrates and byproducts across different cell types and conditions, is an important direction for future research.

3. POLYAMINES IN BRAIN DEVELOPMENT AND FUNCTION

Polyamines are critical regulators of multiple cellular and molecular processes necessary for brain development, maintenance, and adaptive responses throughout life. Polyamines’ abundance and distribution vary across developmental stages and brain regions [16,47–50], reflecting their involvement in processes such as neural proliferation, differentiation, and synaptic function [51–54]. Neurons, astrocytes, oligodendrocytes, and neural progenitor cells all depend on precise regulation of polyamine biosynthesis, catabolism, and transport to maintain cellular homeostasis.

3.1. General cellular activities

3.1.1. Epigenetic modification

Polyamine metabolism intersects with epigenetic regulation by modulating both the availability of key metabolic substrates and the activity of chromatin-modifying enzymes. The aminopropyl donor for polyamine biosynthesis, dcSAM, is produced through AMD1-catalyzed decarboxylation of S-adenosylmethionine (SAM) [28,29]. Because SAM also serves as the universal methyl group donor for DNA and protein methyltransferases, AMD1 activity effectively competes with methyltransferases for SAM utilization, thereby reshaping the global DNA and histone methylation landscape [55,56]. Similarly, SAT1-mediated polyamine acetylation consumes acetyl-CoA, the same acetyl group donor for protein acetylation, and consequently creates a competitive balance that influences histone acetylation states [57,58]. Furthermore, another layer of epigenetic control occurs through polyamines’ direct inhibition of histone acetyltransferases [59–61]. Through these interconnected mechanisms, polyamine metabolism exerts broad regulatory effects on transcriptional programs governing cellular growth, differentiation, plasticity, and stress adaptation (Fig 2).

Figure 2 ∣.

Polyamine metabolism in the brain. Polyamines interact with DNA, RNA, and associated proteins, and consequently modulate chromatin structure, transcription, mRNA transport, stability, and translation. Spermidine-dependent hypusination of eIF5A further regulates the translation of specific proteins. Polyamination, the covalent conjugation of polyamines to glutamine residues on selected proteins, modulates protein interactions and activities. Polyamines also directly bind and regulate the functions of ion channels and neurotransmitter receptors. Polyamine metabolism intersects with methionine, acetyl-CoA, and oxidative stress pathways in both neurons and glia. Modulators of these steps are promising therapeutic candidates. The diagram was created with BioRender.

3.1.2. Hypusination

Hypusination is a unique and highly conserved post-translational modification that occurs exclusively on a single lysine residue (Lys50) of eukaryotic translation initiation factor 5A (eIF5A) [62]. This two-step enzymatic process links polyamine metabolism to protein synthesis and cellular growth (Fig 2). In the first step, deoxyhypusine synthase (DHPS) catalyzes the transfer of an aminobutyl moiety from spermidine to the ε-amino group of the target lysine residue on the eIF5A precursor, thereby forming deoxyhypusine [63]. In the second step, deoxyhypusine hydroxylase (DOHH) hydroxylates the intermediate and generates mature hypusinated eIF5A [64,65]. The hypusine modification is essential for the structural stability and functional activation of eIF5A, by enabling it to promote translation elongation, particularly of polyproline-rich and otherwise difficult-to-translate sequences [66]. Hypusinated eIF5A participates in diverse cellular processes including cell proliferation, autophagy, mitochondrial function, and stress response [67–70]. Given its reliance on spermidine availability, hypusination is a critical biochemical link between polyamine metabolism and the regulation of protein synthesis and cellular homeostasis.

3.1.3. Polyamination

Polyamination is a post-translational modification in which polyamines, primarily spermidine or spermine, are covalently attached to specific glutamine or lysine residues of target proteins, thereby altering their charge, structure, and functional properties (Fig 2). This reaction is typically catalyzed by transglutaminases, which mediate the formation of stable amide bonds between the γ-carboxamide group of glutamine residues and the primary amine groups of polyamines [71]. Through this process, protein mono-or bis-polyamination results in crosslinking or stabilization of protein complexes [72]. Polyamination enhances protein resistance to proteolytic degradation, modulates protein–protein and protein-nucleic acid interactions, and influences cytoskeletal organization and cellular stress responses [73–75]. For example, polyamination of cytoskeletal proteins such as tubulin and actin promotes filament stability [73], whereas modification of transcriptional regulators and enzymes can alter their activity or subcellular localization [75]. Because polyamines are highly charged and closely interact with macromolecules, polyamination enables cells to dynamically regulate structural integrity and signaling functions in response to metabolic or environmental cues [76].

3.1.4. Autophagy

Polyamines play multifaceted roles in autophagy regulation, by acting as both signaling molecules and metabolic modulators. Spermidine, the most extensively studied polyamine, is a potent natural inducer of autophagy across species, including yeast and mammals [59,77]. Spermidine promotes autophagic flux primarily through inhibiting histone acetyltransferases, thus leading to global hypoacetylation of histones and activation of autophagy-related gene expression [60,78]. This epigenetic regulation facilitates the maintenance of cellular homeostasis and enhances longevity by enhancing the clearance of damaged organelles and misfolded proteins. In addition, polyamines influence the activity of key signaling pathways involved in autophagy, such as mTOR and AMPK, and modulate the acetylation status of cytoplasmic proteins essential for autophagosome formation [78,79]. Through these mechanisms, polyamines act as crucial metabolic regulators that link nutrient sensing, stress response, and cellular quality control processes.

3.1.5. Mitochondria

Polyamines are closely associated with mitochondrial metabolism, through roles including stabilizing mitochondrial membranes, promoting oxidative phosphorylation, and protecting mitochondrial DNA against oxidative damage [80–82]. Spermidine supports the tricarboxylic acid cycle and ATP production by modulating key metabolic enzymes [83]. In addition, polyamines induce mitophagy, a specific form of autophagy targeting mitochondria, which clears damaged mitochondria and preserves neuronal energy homeostasis [67,68]. Disruption of polyamine levels leads to mitochondrial fragmentation, decreased membrane potential, and heightened sensitivity to apoptotic stimuli. These mitochondrial effects are particularly relevant in aging and neurodegeneration, in which mitochondrial dysfunction is a hallmark.

3.2. Brain-specific activities

3.2.1. Neurodevelopment

Polyamines regulate neural progenitor proliferation, neuronal differentiation, and migration, by modulating gene expression in neurogenesis and the cell cycle of neural stem cells [52,84]. Experimental depletion of polyamines disrupts cortical layering and impairs dendritic arborization, whereas polyamine supplementation, particularly with spermidine, rescues developmental deficits [85,86]. Polyamines also participate in axon guidance and synapse formation, partly through their effects on cytoskeletal dynamics and cell adhesion molecules [54,87]. Beyond early development, they remain necessary for maintaining neurogenic niches in the adult brain, such as the subventricular zone and hippocampal dentate gyrus [52].

3.2.2. Synaptic plasticity

One of the best-characterized roles of polyamines is their ability to modulate synaptic transmission. Polyamines directly interact with ligand-gated ion channels, particularly NMDA and AMPA receptors, thereby altering receptor gating, desensitization, and conductance properties [54,88,89]. These interactions affect long-term potentiation and long-term depression, two key processes underlying learning and memory. Beyond their postsynaptic effects, polyamines help preserve presynaptic organization and neurotransmitter release dynamics. Studies in Drosophila have shown that dietary spermidine supplementation counteracts age-dependent alterations in synaptic active zones, specialized presynaptic structures responsible for vesicle release, by preventing their enlargement and excessive vesicle exocytosis [90]. These changes restore normal synaptic efficacy and memory performance in aged flies. Similar mechanisms may operate in mammalian neurons, in which polyamines maintain synaptic balance and prevent hyperexcitability. Through these integrated effects on receptor function, ion channel modulation, and presynaptic architecture, polyamines are key regulators of synaptic plasticity and neuronal resilience across species.

3.2.3. Pain perception

Polyamines in the brain have emerged as important modulators of pain perception, acting through their interactions with excitatory neurotransmission and synaptic plasticity. Endogenous polyamines, such as spermine and spermidine, regulate the activity of NMDA receptors, particularly at the NR2B subunit, where they bind an allosteric “polyamine site” that enhances receptor function and calcium influx [91–93]. This modulation facilitates central sensitization processes in brain regions critical for pain processing, including the anterior cingulate cortex, amygdala, and periaqueductal gray. In experimental studies, administration of NMDA receptor antagonists selective for the polyamine-binding site, such as ifenprodil, decreases pain-related aversion when injected into the anterior cingulate cortex; these findings implicate local polyamine-NR2B signaling in the affective dimension of pain [94]. Additionally, observations that alterations in brain polyamine metabolism are associated with heightened neuronal excitability and plasticity within pain pathways have suggested roles in the persistence and emotional amplification of chronic pain [95,96]. Collectively, these findings indicate that polyamines act as neuromodulators within the brain’s pain matrix, by influencing both the sensory and affective components of pain through NMDA receptor-dependent synaptic mechanisms.

4. POLYAMINES IN NEUROLOGICAL DISEASES

Altered polyamine homeostasis is increasingly recognized as both a cause and consequence of neurological disease. Dysregulation can arise from genetic mutations in polyamine metabolic enzymes/transporters, environmental stressors, aging, or secondary responses to neuronal injury. These changes affect multiple cellular processes, including gene expression, redox balance, ion channel regulation, mitochondria, and autophagy, thereby contributing to disease onset and progression.

4.1. Neurological disorders caused by mutations in polyamine metabolic enzymes/transporters

4.1.1. BABS

BABS is a rare congenital neurodevelopmental disorder caused by gain-of-function mutations in the ODC1 gene, which encodes the rate-limiting enzyme in polyamine biosynthesis. These mutations increase ODC1 stability and enzymatic activity, and consequently result in elevated intracellular putrescine and disrupted polyamine homeostasis [19,97]. Clinically, individuals with BABS exhibit global developmental delay, hypotonia, macrocephaly, distinctive craniofacial features, sparse or absent hair, and variable intellectual disability [19,20]. The disorder highlights the critical importance of regulated polyamine metabolism in normal neurodevelopment and cellular growth. Notably, treatment with difluoromethylornithine, an irreversible inhibitor of ODC1, has shown potential in normalizing polyamine levels and improving some clinical outcomes, thus providing a mechanistic basis for targeted therapy [97].

4.1.2. SRS

SRS is an X-linked recessive neurodevelopmental disorder caused by loss-of-function mutations in the SMS gene, which encodes the enzyme responsible for catalyzing the conversion of spermidine to spermine in the terminal step of polyamine biosynthesis. SMS deficiency results in a characteristic imbalance of intracellular polyamines, marked by elevated spermidine and diminished spermine levels, and disruption of multiple cellular processes that depend on proper polyamine homeostasis [21,22,98,99]. Clinically, individuals with SRS typically show intellectual disability, hypotonia, delayed motor development, skeletal abnormalities such as osteoporosis and scoliosis, facial dysmorphism, and muscle weakness [100–108]. Our work has revealed that, at the cellular level, SRS fibroblasts and animal models exhibit elevated oxidative stress, mitochondrial dysfunction, and altered autophagy; these findings reflect the widespread importance of spermidine/spermine balance in maintaining metabolic and structural integrity [22,58]. The study of SRS has provided key insights into the physiological roles of polyamine metabolism in neuronal development, bone homeostasis, and energy metabolism, and continues to provide a model for understanding how perturbations in polyamine balance contribute to human disease.

4.1.3. ATP13A2-related disorders

ATP13A2-related disorders are neurodegenerative conditions caused by mutations in the ATP13A2 gene [109], which encodes a lysosomal P5B-type ATPase that regulates the transport of polyamines and divalent cations such as Mn²⁺ and Zn²⁺. ATP13A2 plays a crucial role in maintaining intracellular polyamine homeostasis by mediating the sequestration and export of spermidine and spermine from lysosomes, thereby preventing their toxic accumulation and preserving organellar integrity. Loss-of-function mutations in ATP13A2 disrupt lysosomal polyamine transport, and consequently lead to polyamine imbalance, lysosomal membrane instability, impaired autophagic flux, and secondary mitochondrial dysfunction [23]. These cellular perturbations culminate in progressive neuronal degeneration, particularly within dopaminergic and pyramidal pathways. Clinically, ATP13A2 mutations are associated with Kufor-Rakeb syndrome, a juvenile-onset form of Parkinson’s disease characterized by parkinsonism, spasticity, cognitive decline, and cerebellar ataxia, as well as with neuronal ceroid lipofuscinosis and hereditary spastic paraplegia type 78 [110,111]. The emerging recognition of ATP13A2 as a lysosomal polyamine transporter underscores a direct mechanistic link between polyamine dysregulation and neurodegeneration, and suggests that polyamine metabolism and transport might be promising therapeutic targets for ATP13A2-associated diseases and related synucleinopathies [112].

4.2. Neurological disorders caused by mutations in hypusination enzymes

Genetic disorders arising from dysregulation of hypusination highlight the essential role of this unique post-translational modification in human development and cellular homeostasis. Hypusination occurs exclusively on eIF5A through a two-step process catalyzed by DHPS and DOHH, by using spermidine as an aminobutyl donor [113]. Pathogenic variants in DHPS or DOHH disrupt this modification and lead to a group of neurodevelopmental syndromes collectively termed hypusination-related disorders [114,115]. Affected individuals typically show global developmental delay, intellectual disability, hypotonia, epilepsy, microcephaly, and distinctive facial or skeletal features. At the cellular level, impaired hypusination compromises eIF5A function in translation elongation, particularly for polyproline-rich proteins, and disrupts key processes such as mitochondrial function, autophagy, and neuronal differentiation [116–118]. Studies in cellular and animal models have further indicated that defective hypusination alters protein homeostasis and metabolic balance. Together, these disorders underscore the indispensable role of hypusination in coordinating translational control with neurodevelopmental and metabolic integrity.

4.3. Common neurological disorders with dysregulated polyamine homeostasis

4.3.1. AD

Polyamine metabolism appears to be actively rewired in AD. Targeted metabolomics analyses have indicated elevated spermidine in the inferior temporal gyrus, as well as close positive associations of spermidine with both neuritic plaque burden and neurofibrillary pathology, thus indicating enhanced flux through transmethylation/polyamine pathways in the affected cortex [119]. mRNA and protein analyses have further identified AZIN2 as among the most strongly elevated polyamine regulators in the brain in AD. Moreover, experimental AZIN2 overexpression in mice with tauopathy has been found to drive higher phospho-tau and insoluble tau species, as well as accompanying anxiety-like behavior and memory deficits, in agreement with a maladaptive “polyamine stress response” that accelerates tau pathology [14]. Glial polyamine metabolism adds another disease-relevant node. In AD-like conditions, astrocytes switch on a urea cycle that funnels ornithine to putrescine via ODC1, thus generating GABA and toxic byproducts that impair memory [120]. In contrast, ODC1 silencing normalizes inhibitory tone and restores memory performance in APP/PS1 mice, thereby supporting astrocytic ODC1 as a potential therapeutic target in polyamine-derived pathology. Our recent work has linked SMS to proteostasis in tauopathy. Whereas modest SMS elevation is observed in AD brain proteomics, half reduction of SMS enhances autophagic flux and decreases Tau accumulation in neuronal and glial models [24]. Collectively, these studies have established an important role of polyamine metabolism in AD pathogenesis. However, whether its dysregulation serves as an initiating trigger, a secondary amplifying factor, or a downstream consequence of the disease remains unclear. This uncertainty likewise applies to other complex neurological disorders, as discussed below.

4.3.2. PD

Polyamines play multifaceted roles in PD pathology, by integrating metabolic, proteostatic, and neuronal-survival pathways. Epidemiological and biomarker studies have indicated that polyamine levels in patients with PD correlate with disease progression and clinical subtypes [121,122]. Supporting these observations, a disease-associated decrease in the expression of SAT1, the rate-limiting enzyme of polyamine catabolism, has been reported in the dorsal motor nucleus of the vagus of the brain in PD. Functional studies across yeast, mouse, and human systems have demonstrated that decreased SAT1 activity increases intracellular spermidine and spermine, and promotes α-synuclein aggregation and toxicity, whereas pharmacological activation of SAT1 with DENSPM mitigates α-synuclein pathology and neurodegeneration [25]. These findings highlight a protective role of balanced polyamine turnover. Building on these findings, recent work in a Drosophila α-synucleinopathy model has revealed that genetic manipulation of polyamine-interconversion enzymes affects α-synuclein accumulation, motor function, and lifespan, thus further emphasizing that polyamine homeostasis is a key modulator of α-synuclein toxicity [123]. Finally, loss of ATP13A2, a lysosomal polyamine transporter, leads to intracellular polyamine accumulation, impaired autophagic clearance, and α-synuclein aggregation; consequently, polyamine dysregulation is linked to lysosomal dysfunction [23,112]. In summary, these studies indicate substantial involvement of polyamine metabolism/transport in PD pathogenesis.

4.3.3. HD

Growing evidence indicates that polyamine metabolism is dysregulated in HD and may play an active role in disease pathogenesis. Postmortem analyses of human HD brains have revealed diminished spermine levels in the putamen, a region that undergoes extensive neurodegeneration in HD; these findings suggest an association between altered polyamine homeostasis and striatal vulnerability [124]. In agreement with a potential neuroprotective role of polyamines, pharmacological supplementation with spermidine or spermine in chemically induced HD animal models, such as 3-nitropropionic acid-treated rodents, attenuates striatal neuroinflammation, normalizes neurotransmitter imbalances, and improves recognition memory deficits [125,126]. In contrast, mechanistic studies have demonstrated that mutant huntingtin containing pathologically expanded polyglutamine (polyQ) tracts directly perturbs arginine and polyamine metabolism. Expression of mutant huntingtin upregulates arginase 1 and diverts arginine metabolism away from nitric oxide synthesis toward enhanced polyamine production. Reciprocally, elevated intracellular spermine promotes aggregation of polyQ-expanded huntingtin and exacerbates polyQ-mediated cytotoxicity [26]. Collectively, these findings highlight a complex, context-dependent role of polyamines in HD, in which both polyamine deficiency and excess may be detrimental. These bidirectional effects underscore the importance of tight spatial and temporal regulation of polyamine metabolism in the nervous system, and further suggest that dysregulated polyamine flux might contribute to HD progression through multiple, and potentially opposing, mechanisms.

4.3.4. Ataxia

Evidence from chemically induced models supports a link between polyamines and ataxia. Administration of neurotoxins such as kainic acid, which provokes cerebellar damage and motor incoordination, produces a pronounced increase in brain polyamine levels, particularly putrescine, across multiple brain regions [127]. This elevation reflects both enhanced ornithine decarboxylase activity and a compensatory response to neuronal injury, and suggests that polyamine metabolism is dynamically engaged during cerebellar stress. Complementary findings from genetic models have further underscored the pathological consequences of disturbed polyamine turnover. In mice lacking both SMOX and SAT1, key enzymes responsible for polyamine catabolism, progressive ataxia develops alongside Purkinje cell loss, gliosis, neuroinflammation, and demyelination [13]. These changes coincide with altered spermidine/spermine ratios, elevated transglutaminase 2 activity, and accumulation of polyaminated α-synuclein aggregates in the cerebellum. Pharmacological inhibition of transglutaminase alleviates these phenotypes, thus confirming that excessive polyamine cross-linking contributes to neuronal toxicity. Together, these studies demonstrate that both increased synthesis and impaired degradation of polyamines can disrupt cerebellar integrity, and highlight polyamine homeostasis as a critical determinant of motor coordination and cerebellar health.

4.3.5. Psychiatric disorders

Accumulating evidence implicates dysregulation of polyamines and their metabolic pathways in major psychiatric disorders, including depression, schizophrenia, and suicidal behavior. Early biochemical studies in schizophrenia indicated altered levels of spermidine and spermine and abnormal activities of polyamine-associated enzymes in patient-derived cells and postmortem brain tissue [128,129]. In mood disorders, particularly major depressive disorder, alterations in peripheral and central polyamine levels have been consistently observed, alongside changes in the arginine-agmatine-polyamine axis, a pathway implicated in the regulation of glutamatergic neurotransmission, stress responses, and neuroplasticity [130,131]. Notably, a critical postmortem study of people who died by suicide has provided direct evidence of cortical polyamine dysregulation, including significant alterations in putrescine, spermidine, and spermine concentrations across multiple regions of the cerebral cortex, comprising motor, dorsolateral, and orbitofrontal areas [18]. This biochemical phenotype is accompanied by marked SAT1 downregulation, as revealed by genome-wide expression analyses of the ventral prefrontal cortex, a brain region critically involved in mood regulation and suicidal behavior; moreover, complementary genetic and epigenetic studies have further implicated SAT1 dysregulation in suicide and major depression [132,133]. Collectively, these findings suggest that impaired polyamine homeostasis might be a convergent molecular mechanism linking mood dysregulation, altered stress adaptation, and suicidal vulnerability. Polyamine metabolism therefore might potentially provide a source of biomarkers and therapeutic targets in psychiatric diseases.

4.3.6. Brain tumors

Polyamines and their metabolic pathways are markedly dysregulated in brain tumors, and play critical roles in tumor growth and malignancy. Large-scale biochemical analyses of more than 600 primary human brain tumors have demonstrated significantly greater ODC1 activity in gliomas than adjacent non-neoplastic brain tissue [134,135]. Whereas ODC1 activity correlated with histological malignancy grade, the levels of putrescine, spermidine, and spermine varied by tumor type and location, thus indicating tumor-specific polyamine metabolism changes in vivo [134,135]. In agreement with these clinical observations, brain tumor stem cells exhibit a marked dependency on elevated polyamine synthesis: elevated expression of biosynthetic enzymes, including ODC1, is required to maintain stem-like properties and sustain tumor growth [136]. In parallel, in glioblastoma (GBM), a highly aggressive form of glioma, elevated intracellular levels of the polyamine spermidine in tumor tissue and the tumor microenvironment promote tumor progression in preclinical models by suppressing antitumor cytotoxic CD8⁺ T cell function and skewing the immune milieu toward immunosuppression [137]. Genetic knockdown of ODC1 extends survival in mouse glioma models and partially reverses this immunosuppressive phenotype; therefore, tumor-derived polyamines support malignancy partly through immunomodulation rather than solely through intrinsic growth effects [137]. Dysregulation of polyamine catabolic pathways has also been implicated: the elevated SAT1 expression observed in GBM contributes to tumor cell radio resistance and might be a vulnerability that sensitizes tumors to genotoxic therapies [138]. Together, these studies have established elevated polyamine flux as a defining metabolic feature of brain tumors, and they support that polyamine metabolism might be a tractable target for therapeutic intervention.

4.3.7. Stroke and traumatic brain injury

Polyamine homeostasis is perturbed by injury to the brain. In rodent models of cerebral ischemia and traumatic brain injury, ODC1 mRNA and protein levels are markedly elevated at injury sites, and correlate with elevated putrescine levels [139,140]. In contrast, spermidine and spermine levels remain relatively unchanged, because of the downregulation of dcSAM that is required for conversion of spermidine to spermine. Concurrently, increased activity of SAT1, SMOX, and PAOX generates cytotoxic by-products including hydrogen peroxide and reactive aldehydes. These metabolites have been implicated in neuronal necrosis, reactive gliosis, disruption of the integrity of the blood-brain barrier, and cerebral edema. Furthermore, brain injury is accompanied by excessive release of the neurotransmitter glutamate, which causes excitotoxicity. Elevated polyamine levels have been postulated to exacerbate these processes by binding and potentiating NMDA receptors, thereby amplifying calcium influx and aggravating excitotoxic neuronal damage. In support of this mechanism, ifenprodil, a noncompetitive antagonist of NMDA receptors that acts by binding polyamine sites, has been found to attenuate edema formation and disruption of the blood-brain barrier in a rat model of traumatic brain injury [141,142].

Overall, polyamine dysregulation is a convergent mechanism underlying diverse neurological conditions. Its widespread effects on cellular function underscore the potential of polyamine metabolism as a diagnostic biomarker and therapeutic target.

5. THERAPEUTIC IMPLICATIONS AND FUTURE DIRECTIONS

Given the pervasive influence of polyamine metabolism on neuronal homeostasis, targeting this pathway offers unique therapeutic opportunities across a wide spectrum of neurological and neurodegenerative diseases (Fig 2). Because polyamines are involved in cellular processes as diverse as chromatin remodeling, mitochondrial bioenergetics, and autophagy, therapeutic modulation must be precisely tailored to restore balance without compromising essential physiological functions.

5.1. Enzyme-targeted interventions

Several metabolic enzymes in the polyamine pathway are being actively investigated as therapeutic targets. The irreversible ODC1 inhibitor difluoromethylornithine has demonstrated clinical benefit in ODC1-related BBAS by normalizing putrescine levels and ameliorating developmental phenotypes, thus providing a proof of concept for enzyme-directed therapy [97]. Our work in a Drosophila model and SRS patient cells has indicated that phenylbutyrate-mediated SAT1 destabilization decreases oxidative stress, and partially restores mitochondrial and autophagy function [58]. In neurodegenerative disease models, modulating key enzymes of polyamine interconversion has shown protective effects. Ablation of SAT1 in a mouse model alters Tau phosphorylation and mitigates select features of tauopathy [143], whereas inhibition of ODC1 in astrocytes alleviates memory impairment in AD models by decreasing putrescine-derived GABA accumulation [120]. Our recent work in tauopathy models has revealed that a partial decrease in SMS, the enzyme catalyzing the final step of spermine synthesis, enhances autophagic flux, decreases Tau accumulation, and improves neuronal and behavioral outcomes [24]. Therefore, fine-tuning polyamine synthesis, rather than complete inhibition, might potentially restore proteostasis and neuronal resilience. Collectively, these results highlight that selective activation or suppression of specific polyamine metabolic steps offers a rational strategy to rebalance polyamine flux in a disease-dependent manner.

5.2. Polyamine supplementation and mimetics

Nutritional and pharmacological supplementation, particularly with spermidine, has shown promising neuroprotective and anti-aging effects by enhancing autophagy, mitochondrial efficiency, and synaptic plasticity [144]. Spermidine-enriched diets and analogues (e.g., spermidine trihydrochloride) are currently being evaluated in early clinical trials for cognitive decline and AD, in which they have demonstrated improvements in memory performance and reductions in neuroinflammatory markers [52,145,146]. Synthetic polyamine analogues, such as DENSPM and PG-11047, mimic the structure of natural polyamines while redirecting metabolic flux and limiting oxidative toxicity; therefore, these treatments might offer potential therapeutic benefits in neurodegenerative conditions associated with oxidative stress or protein aggregation [147,148].

5.3. Targeting polyamine transport and compartmentalization

The discovery of ATP13A2 and ATP13A3 as lysosomal polyamine transporters has provided new therapeutic targets for correcting intracellular distribution defects [23,36]. Small-molecule modulators that enhance lysosomal polyamine export or restore ATP13A2 function might potentially reverse accumulation-associated autophagic dysfunction in Parkinson’s disease and related lysosomal disorders. Additionally, the role of SLC45A4 in coupling polyamine transport to neuronal pH regulation highlights another potential target for modulating nociception and excitability [37].

5.4. Integrative metabolic and epigenetic modulation

Polyamine flux is tightly associated with methionine and acetyl-CoA metabolism, both of which influence chromatin state and gene expression [55,56,58,149]. Therefore, combined approaches that restore polyamine balance and normalize SAM-dependent methylation or acetyl-CoA-dependent acetylation might synergistically reestablish transcriptional and metabolic homeostasis. Such integrative strategies might be particularly beneficial in age-related neurodegenerative disorders, in which epigenetic and metabolic dysregulation converge.

Future research should use metabolomics, single-cell transcriptomics, and spatial imaging to resolve region-and cell type-specific dynamics of polyamine metabolism in the brain. Because polyamine levels and enzyme activities vary among individuals and disease stages, precision-medicine frameworks combining polyamine profiling with genetic background (e.g., ODC1, SMS, and ATP13A2 variants) will be critical for patient stratification and treatment optimization. The development of non-invasive biomarkers, such as circulating or CSF polyamine signatures, would further enable real-time monitoring of therapeutic efficacy and disease progression. Advances in targeted and untargeted metabolomics now allow for reliable quantification of putrescine, spermidine, spermine, and acetylated polyamines in accessible biofluids, such as blood and cerebrospinal fluid, and multiple studies have reported disease-associated alterations across neurodegenerative, neuropsychiatric, and neuro-oncological conditions [121,131,137,150–152]. However, current evidence is largely derived from cross-sectional or modestly sized cohorts; moreover, because polyamine measures are influenced by age, diet, microbiome composition, systemic inflammation, and comorbidities, they have limited specificity as standalone diagnostic markers [153–156]. Consequently, polyamines are best currently viewed as context-dependent biomarkers with greater utility for disease monitoring, pharmacodynamic assessment, and longitudinal tracking of therapeutic response than for primary diagnosis. Ongoing efforts incorporating longitudinal sampling, standardized analytical platforms, and multimodal integration with genetics, imaging, and clinical phenotyping are expected to clarify the robustness and clinical relevance of polyamine-based signatures. Although polyamine metabolism has not yet achieved routine clinical validation, it is a biologically grounded, technically tractable biomarker class with strong potential for future translation as part of composite biomarker panels in neurology.

In summary, therapeutic manipulation of polyamine metabolism is an emerging frontier in neuromodulatory therapy. Continued interdisciplinary research integrating biochemical, neurogenetic, and pharmacological approaches will be essential to translate the expanding understanding of polyamine biology into effective interventions for neurodevelopmental and neurodegenerative disorders.