Saposin C: Neuronal Effect and CNS Delivery by Liposomes

• Published in: Annals of the New York Academy of Sciences 2005-08, Vol.1053 (1), p.237-246
• Main Authors: CHU, ZHENGTAO, SUN, YING, KUAN, CHIA YI, GRABOWSKI, GREGORY A., QI, XIAOYANG
• Format: Article
• Language: English
• Subjects: Animals; blood-brain barrier; Brain - metabolism; Cells, Cultured; Central Nervous System - cytology; Central Nervous System - metabolism; Cerebral Cortex - cytology; Cerebral Cortex - metabolism; Drug Carriers; Drug Delivery Systems; Fibroblasts - metabolism; Fluorescent Antibody Technique; Humans; Injections, Intravenous; liposome; Liposomes; Mice; Mice, Knockout; Microscopy, Electron; multivesicular body; Neurodegenerative Diseases - genetics; Neurons - metabolism; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - pharmacokinetics; phosphatidylserine; prosaposin; Saposins - administration & dosage; Saposins - genetics; Saposins - pharmacokinetics
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1111/j.1749-6632.2005.tb00031.x

: 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.