Saposin C: Neuronal effect and CNS delivery by liposomes
Saposin C: Neuronal effect and CNS delivery by liposomes
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DOI：
10.1196/annals.1344.021
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发表时间：
2005-01-01
期刊：
影响因子：
--
通讯作者：
Qi, XY
中科院分区：
文献类型：
--
作者：
Chua, ZT;Sun, Y;Qi, XY
皂苷C是四种小的脂质结合蛋白中的一种，它们来源于一种名为prosaposin （PSAP）的前体蛋白。PSAP具有多种神经元效应，包括刺激神经突生长、神经元保存和神经再生增强。PSAP的神经营养功能所需的最小结构域位于皂苷c的氨基末端一半。人类和小鼠PSAP基因的遗传缺陷导致复杂的溶酶体贮积病。PSAP-和皂苷c缺乏患者的皮肤成纤维细胞有大量的多泡体（MVBs）积聚。将外源性含皂苷c脂质体掺入培养的PSAP-/-细胞中，可使积累的MVBs降至正常水平。内化皂苷C定位于晚期核内体和溶酶体。MVBs对于维持神经元发育和生长所需的细胞动态平衡至关重要。PSAP-/-小鼠寿命短（30天），中枢神经系统（CNS）神经元变性。与PSAP-/-成纤维细胞类似，PSAP缺失小鼠的CNS神经元和脑组织中积累了过量的MVBs。PSAP-/-小鼠培养的皮质和海马神经元存活率较低，并表现出神经突退行性模式。通过静脉注射二油酰磷脂酰丝氨酸（DOPS）脂质体，皂苷C在体外通过培养的神经元和在体内通过血脑屏障进入小鼠脑神经细胞。这些研究可能为神经元的保护、保存和再生提供一种新的治疗方法。
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 bomeostasis 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.