Polyamines across neurodegenerative proteinopathies.

Polyamines (PAs) are evolutionarily conserved metabolites that connect protein quality control with lysosomal, mitochondrial, and redox homeostasis. Their metabolism is situated at a critical intersection of cell-sustaining and neurodegenerative pathways. Here, we synthesize evidence across Alzheimer's disease, Parkinson's disease, polyglutamine repeat disorders, amyotrophic lateral sclerosis, and multiple system atrophy, each of which differ in vulnerability to changes in PA metabolism. Although previous reviews have investigated polyamines in individual neurodegenerative disorders, few have compared their roles across the broader spectrum of neurodegenerative proteinopathies. Here, we address this gap by synthesizing evidence across multiple diseases to examine how PAs influence disease-associated protein aggregation and clearance, and how these effects depend on PA species, concentration, cellular context, disease stage, subcellular localization, redox state, and lysosomal and mitochondrial capacity. Human tissue and biofluid studies report disease-associated changes in PA metabolites, pathway enzymes, and transporter remodeling, as a function of neurodegenerative disorders. Mechanistic studies reveal that spermidine and spermine can alter the assembly, condensation, compartmentalization, and clearance of various neurotoxic proteins, whereas the effects of putrescine are more system- and concentration-dependent. These effects engage both shared pathways and distinct mechanisms, depending on protein identity, cell type, and subcellular location. Curiously, PA manipulation may be protective in one context yet harmful in another. The framework that we propose can distinguish adaptive remodeling from pathogenic dysregulation and can guide disease-relevant therapeutic strategies.