Polyamines are ubiquitous aliphatic polycations, meaning they carry multiple positive charges that allow them to bind avidly to negatively charged molecules throughout the cell. This electrochemical versatility explains their astonishing range of functions. Polyamines regulate how nucleic acids fold and interact, modulate the activity of ion channels in neuronal membranes, govern autophagy, the cellular recycling system, maintain redox balance, support proteostasis, and shape immune signaling pathways. In healthy tissue, the concentrations of putrescine, spermidine, and spermine are controlled with exquisite precision by an interconnected network of biosynthetic enzymes such as ornithine decarboxylase, spermidine synthase, and spermine synthase, catabolic enzymes including spermine oxidase and polyamine oxidase, the acetylation enzyme spermidine/spermine-N1-acetyltransferase 1, and a dedicated polyamine transport system that shuttles these molecules across cellular compartments.

The review details how disruption of each node in this network has been linked to neurological disease. In Alzheimer’s disease, altered polyamine flux intersects directly with the two hallmark protein pathologies. Recent work has shown that aberrant activity of antizyme inhibitor 2 and the resulting polyamine imbalance can precipitate tau neuropathology, while separate studies found that reducing spermine synthase activity enhances autophagy and thereby suppresses tau accumulation. Targeted metabolomic and transcriptomic analyses of Alzheimer’s patients have revealed dysregulation across multiple metabolic networks involving brain transmethylation and polyamine pathways, and single-cell metabolomics of ageing and Alzheimer’s brains has now mapped distinctive polyamine signatures in microglia, astrocytes, and neurons. The picture that emerges is one of a metabolic system pushed off balance, with excess spermine and its oxidation products contributing to oxidative stress and impaired autophagic clearance of toxic protein aggregates.

Parkinson’s disease tells a complementary story centered on transport and interconversion. The lysosomal transporter ATP13A2, mutations in which cause the inherited Kufor-Rakeb syndrome, a form of early-onset parkinsonism, has been shown to export polyamines from lysosomes. When this transporter fails, polyamines accumulate inside lysosomes, contributing to lysosomal dysfunction, mitochondrial oxidative stress, and heightened vulnerability of dopaminergic neurons to alpha-synuclein toxicity. Structural studies of human ATP13A2 have revealed the molecular basis of its polyamine transport activity, and experiments in fruit flies have demonstrated that manipulating polyamine interconversion enzymes such as SAT1 can directly alter alpha-synuclein levels and toxicity. Metabolomic studies in Parkinson’s patients have independently identified polyamine-related signatures associated with diagnosis and clinical severity, strengthening the case that these pathways are not merely bystanders but active participants in the disease process.

Beyond the two most common neurodegenerative disorders, the review catalogues polyamine involvement across a striking breadth of conditions. In amyotrophic lateral sclerosis, dysregulated polyamine metabolism contributes to muscle fiber vulnerability, and alterations in ornithine decarboxylase activity have been documented in mouse models of motor neuron degeneration. Interestingly, spermidine supplementation has shown beneficial transcriptomic effects in ALS mouse models, and modulation of histone methylation by spermidine has improved motor neuron survival, highlighting the dual character of these molecules. In Snyder-Robinson syndrome, a rare X-linked disorder caused by spermine synthase deficiency, the loss of spermine production leads to lysosomal dysfunction and oxidative stress, producing intellectual disability, muscle and bone abnormalities, and movement problems. Bachmann-Bupp syndrome, caused by mutations in the ornithine decarboxylase gene, has even yielded to targeted therapy, with the polyamine synthesis inhibitor eflornithine used to restore metabolic balance in affected children.

The review also emphasizes roles for polyamine catabolism in epilepsy, cerebral ischemia, and diabetic retinopathy. Transgenic mice overexpressing spermine oxidase in cortical neurons show astrocyte dysfunction and increased susceptibility to epileptic seizures, and neuroinflammation has been shown to promote spermine degradation in temporal lobe epilepsy, contributing to drug resistance. In cerebral ischemia, the spermine oxidation product 3-aminopropanal acts as a potent neurotoxin, and neutralizing it in animal models provides marked neuroprotection. In diabetic retinopathy, spermine oxidase activity drives retinal neurodegeneration, and pharmacological inhibition of this enzyme has preserved visual acuity and retinal function in diabetic mice. These findings collectively suggest that the specific catabolic products of polyamine breakdown, rather than polyamines themselves, may be the critical toxic agents in several contexts.

To organize this sprawling evidence, the authors frame four interconnected mechanistic themes through which polyamine dysregulation damages the nervous system: autophagy, oxidative stress, proteostasis, and neuroinflammation. Spermidine has emerged as a bona fide autophagy inducer, essential even for fasting-mediated autophagy and longevity benefits, and its epigenetic effects on histone modifications appear to underlie some of its neuroprotective actions. Yet the same molecules can generate reactive oxygen species when oxidized by spermine oxidase and polyamine oxidase, producing hydrogen peroxide and reactive aldehydes. Polyamine stress responses triggered by tauopathy and other protein aggregation states further complicate the balance, and polyamine metabolism in immune cells has been shown to promote Th17 polarization and inflammatory disease progression, linking this ancient metabolic pathway to neuroinflammation.

Therapeutically, the review outlines three broad strategies now under investigation. The first is direct spermidine administration, which has reduced neuroinflammation and soluble amyloid-beta in Alzheimer’s mouse models and improved cognitive measures in studies of ageing, though it carries an unresolved risk that autophagy induction could, in some settings, tip toward apoptosis. The second is pharmacological modulation of polyamine-metabolic enzymes and transporters, exemplified by difluoromethylornithine, an inhibitor of ornithine decarboxylase with an established history in oncology and now demonstrated benefit in Bachmann-Bupp syndrome, as well as SMOX inhibition in diabetic retinopathy and phenylbutyrate-mediated modulation of polyamine acetylation in Snyder-Robinson syndrome models. The third involves combination strategies that pair polyamine interventions with autophagy modulation, anti-inflammatory agents, or delivery technologies designed to cross the formidable barrier of the blood-brain barrier.

The authors are careful to stress that polyamines exert both protective and toxic effects depending on concentration, cellular compartment, and disease context, a duality that makes simplistic supplementation or depletion strategies risky. A dose of spermidine that enhances autophagic clearance of alpha-synuclein in one model could, in another cellular compartment or disease stage, fuel the biomolecular condensation processes implicated in the aggregation of tau and alpha-synuclein. Successful translation, the review concludes, will require CNS-relevant biomarkers to track polyamine flux in living patients, careful optimization of dose and route of administration, and explicit attention to blood-brain barrier constraints that determine whether orally or peripherally administered agents can ever reach their neuronal targets. As the global burden of dementia and other neurodegenerative diseases continues to climb, the humble polyamines, once a footnote of cell biology, are now positioned as one of the most mechanistically rich and therapeutically tantalizing frontiers in neuroscience.

Subject of Research: Dysregulated polyamine metabolism in neurological disorders

Article Title: Dysregulated polyamine metabolism in neurological disorders: molecular mechanisms and therapeutic opportunities

Article References: Li, K., Si, Q., Zhang, C., Zhang, C., Wang, M., Liu, J., Zhao, J., Xing, H., & Liu, J. (2026). Dysregulated polyamine metabolism in neurological disorders: molecular mechanisms and therapeutic opportunities. Molecular Biology Reports, 53(1), Article 1602. https://doi.org/10.1007/s11033-026-12774-y

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12774-y

Keywords: polyamine metabolism, spermidine, neurodegeneration, Alzheimer's disease, Parkinson's disease, autophagy, oxidative stress, tauopathy, ATP13A2, spermine oxidase, therapeutic targets, neurological disorders