Beyond the classic AD and PD links, polyamine dysregulation is tied to ALS, Snyder-Robinson syndrome, and Bachmann-Bupp syndrome, with spermidine showing beneficial transcriptomic effects and therapies targeting metabolism restoring balance.

A cautious translation is essential given context-dependent protective versus toxic effects of polyamines, requiring CNS-relevant biomarkers, optimized dosing, and strategies to overcome CNS delivery and blood-brain barrier constraints.

Four core mechanisms frame polyamine-related neurodegeneration: autophagy, oxidative stress, proteostasis, and neuroinflammation, with spermidine inducing autophagy but potentially generating reactive species under oxidative conditions.

Overall, polyamine metabolism stands out as a central, mechanistically rich frontier in neurodegenerative research with meaningful therapeutic potential.

Polyamines (putrescine, spermidine, spermine) regulate neuronal function, autophagy, redox balance, proteostasis, and immune signaling, with metabolism governed by a network of enzymes and transporters.

Therapeutic strategies are advancing, including direct spermidine administration, pharmacological modulation of polyamine enzymes/transporters (e.g., DFMO, SMOX inhibitors, acetylation modulation), and combination approaches with autophagy enhancers, anti-inflammatories, or delivery systems to cross the blood-brain barrier.

In Parkinson’s disease, the lysosomal transporter ATP13A2 exports polyamines; its malfunction drives lysosomal dysfunction, mitochondrial oxidative stress, and increased alpha-synuclein toxicity, with structural and Drosophila-model evidence showing modulation via SAT1.

Polyamine catabolism links to epilepsy, cerebral ischemia, and diabetic retinopathy, with toxic byproducts like 3-aminopropanal from spermine oxidation contributing to neuronal damage.

Dysregulated polyamine metabolism relates to Alzheimer’s disease, influencing tau pathology and autophagy, with distinct polyamine signatures observed in microglia, astrocytes, and neurons.