Prosaposin in CNS health and disease, metabolic stress and exercise adaptation

Abstract Prosaposin (PSAP), a highly conserved lysosomal protein and precursor of saposins A–D, has emerged as a key regulator of cellular and central nervous system (CNS) homeostasis. Disrupted PSAP trafficking may lead to amyloid protein aggregation with implications for neurodegenerative diseases. In Alzheimer’s disease (AD) and Parkinson’s disease (PD), PSAP shows altered expression patterns and pathological co-localization with amyloid aggregates. PSAP variants are linked to multiple neurodegenerative diseases, including synucleinopathies, Gaucher’s disease, and metachromatic leukodystrophy. Its levels are elevated in blood and cerebrospinal fluid in some individuals with AD or PD and are upregulated by stress conditions such as nerve injury and cold adaptation, but not by exercise. Prosaptides, short peptides derived from PSAP, show protective effects in models of oxidative stress, CNS injury, and metabolic disorders. Pharmacological stabilization of PSAP interactions with progranulin has shown promise in neurodegenerative disease models. These findings suggest PSAP plays an important role in maintaining brain health and may hold therapeutic potential. Here, we provide a comprehensive overview of PSAP’s role in CNS health and disease, metabolic stress, and exercise adaptation.