Dysregulated polyamine metabolism in neurological disorders: molecular mechanisms and therapeutic opportunities.
Dysregulated polyamine metabolism in neurological disorders: molecular mechanisms and therapeutic opportunities.
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Xinxiang, CN · Author affiliation
Brain Hospital, Henan Medical Key Laboratory of Neurology, Henan Joint International Laboratory of Neurorestoratology for Senile Dementia, Henan Engineering Research Center for Neurorestoratology, Henan Engineering Technology Research Center for Neurorestoratology, Henan Key Laboratory of Neurorestoratology and Protein Modification, The First Affiliated Hospital of Henan Medical University, Xinxiang, 453100, Henan, China.Location evidence
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Original abstract
Polyamines (PAs), principally putrescine (Put), spermidine (Spd), and spermine (Spm), are ubiquitous aliphatic polycations that regulate nucleic-acid interactions, ion-channel activity, autophagy, redox balance, proteostasis, and immune signaling. Growing genetic, multi-omics, and experimental evidence indicates that disruption of PA biosynthesis, catabolism, acetylation, and transport contributes to neurological disease. In Alzheimer's disease (AD), altered PA flux intersects with Tau and amyloid-β (Aβ) pathology, methylation imbalance, oxidative stress, and impaired autophagic clearance. In Parkinson's disease (PD), PA transport and interconversion are linked to lysosomal dysfunction, mitochondrial stress, and α-synuclein toxicity; ATP13A2-associated Kufor-Rakeb syndrome further illustrates the neurological consequences of defective lysosomal PA transport. PA dysregulation is also implicated in amyotrophic lateral sclerosis (ALS), diabetic retinopathy, Snyder-Robinson syndrome, epilepsy, Bachmann-Bupp syndrome, and cerebral ischemia. This review integrates disease-specific evidence with four interconnected mechanisms-autophagy, oxidative stress, proteostasis, and neuroinflammation-and discusses therapeutic approaches including direct Spd administration, modulation of PA-metabolic enzymes and transporters, and combination strategies. Because PAs can exert both protective and toxic effects depending on concentration, cellular compartment, and disease context, translation will require CNS-relevant biomarkers, dose and route optimization, and explicit consideration of blood-brain barrier constraints.