Saposin C: Neuronal Effect and CNS Delivery by Liposomes

Abstract: Saposin C is one of four small lipid‐binding proteins that derive from a single precursor protein, named prosaposin (PSAP). PSAP has several neuronal effects, including neurite outgrowth stimulation, neuron preservation, and nerve regeneration enhancement. A minimal domain required for PSAP's neurotrophic function is located in the amino‐terminal half of saposin C. Genetic defects of the PSAP gene in humans and mice lead to a complex lysosomal storage disease. The skin fibroblasts from PSAP‐ and saposin C‐deficient patients have a massive accumulation of multivesicular bodies (MVBs). Incorporation of exogenous saposin C‐containing liposomes into the cultured PSAP−/− cells reduced the accumulated MVBs to normal levels. Internalized saposin C was localized to late endosomes and lysosomes. MVBs are crucial for maintaining the cellular homeostasis required for neuronal development and growth. PSAP−/− mice have a short life span (30 days) and central nervous system (CNS) neuronal degeneration. Similar to PSAP−/− fibroblasts, excessive MVBs accumulated in CNS neurons and brain tissues of PSAP‐null mice. Cultured cortical and hippocampal neurons from PSAP−/− mice had poor survival and displayed a neurite degenerative pattern. Delivery of saposin C ex vivo into cultured neurons and in vivo into brain neuronal cells in mice across the blood‐brain barrier was accomplished with intravenously administered dioleoylphosphatidylserine (DOPS) liposomes. These studies may yield a new therapeutic approach for neuron protection, preservation, and regeneration.

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