Saposin C: neuronal effect and CNS delivery by liposomes.
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.
Chu
Zhengtao
Z
Division and Program in Human Genetics, Children's Hospital Research Foundation, University of Cincinnati, Ohio 45229-3039, USA.
Sun
Ying
Y
Kuan
Chia Yi
CY
Grabowski
Gregory A
GA
Qi
Xiaoyang
X
D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005347:Fibroblasts / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D019636:Neurodegenerative Diseases / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D049231:Saposins / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics*
D004337:Drug Carriers; D008081:Liposomes; D018696:Neuroprotective Agents; C483344:Psap protein, mouse; D049231:Saposins