Chu Zhengtao, Sun Ying, Kuan Chia Yi, Grabowski Gregory A, Qi Xiaoyang
Division and Program in Human Genetics, Children's Hospital Research Foundation, University of Cincinnati, Ohio 45229-3039, USA.
Ann N Y Acad Sci. 2005 Aug;1053:237-46. doi: 10.1196/annals.1344.021.
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.
鞘脂激活蛋白C是由单一前体蛋白（称为前鞘脂激活蛋白，PSAP）衍生而来的四种小的脂质结合蛋白之一。PSAP具有多种神经元效应，包括刺激神经突生长、保护神经元和增强神经再生。PSAP神经营养功能所需的最小结构域位于鞘脂激活蛋白C的氨基末端一半。人类和小鼠中PSAP基因的遗传缺陷会导致一种复杂的溶酶体贮积病。PSAP和鞘脂激活蛋白C缺陷患者的皮肤成纤维细胞有多泡体（MVBs）的大量积累。将含有外源性鞘脂激活蛋白C的脂质体掺入培养的PSAP-/-细胞中，可将积累的MVBs减少到正常水平。内化的鞘脂激活蛋白C定位于晚期内体和溶酶体。MVBs对于维持神经元发育和生长所需的细胞内稳态至关重要。PSAP-/-小鼠寿命较短（30天），并有中枢神经系统（CNS）神经元变性。与PSAP-/-成纤维细胞类似，PSAP基因敲除小鼠的CNS神经元和脑组织中积累了过多的MVBs。来自PSAP-/-小鼠的培养皮质和海马神经元存活率低，并呈现神经突退化模式。通过静脉注射二油酰磷脂酰丝氨酸（DOPS）脂质体，可在体外将鞘脂激活蛋白C递送至培养的神经元，并在体内将其递送至小鼠脑神经元细胞，穿过血脑屏障。这些研究可能会产生一种新的神经元保护、保存和再生治疗方法。
