Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2
Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2
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DOI：
10.1093/hmg/ddp460
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发表时间：
2009-12-15
影响因子：
3.5
通讯作者：
Meisler, Miriam H.
中科院分区：
文献类型：
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作者：
Ferguson, Cole J.;Lenk, Guy M.;Meisler, Miriam H.
影响PI 3 P转化为信号脂质PI（3，5）P-2的突变导致小鼠脑的海绵状变性，并且与人类疾病Charcot-Marie-Tooth病和肌萎缩性侧索硬化（ALS）相关。我们现在报道了蛋白质LC 3-II、p62和LAMP-2在PI（3，5）P-2调节复合物的两个组分（图4和Vac 14）突变的小鼠的神经元和星形胶质细胞中的积累。细胞质包涵体含有p62和泛素化蛋白存在于突变的大脑发生变性的区域。p62和LAMP-2在受影响细胞中的共定位表明自溶酶体的形成或再循环受损。这些结果确立了PI（3，5）P-2在哺乳动物中枢神经系统（CNS）自噬中的作用，并证明影响PI（3，5）P-2的突变可导致包涵体疾病。
Mutations affecting the conversion of PI3P to the signaling lipid PI(3,5)P-2 result in spongiform degeneration of mouse brain and are associated with the human disorders Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis (ALS). We now report accumulation of the proteins LC3-II, p62 and LAMP-2 in neurons and astrocytes of mice with mutations in two components of the PI(3,5)P-2 regulatory complex, Fig4 and Vac14. Cytoplasmic inclusion bodies containing p62 and ubiquinated proteins are present in regions of the mutant brain that undergo degeneration. Co-localization of p62 and LAMP-2 in affected cells indicates that formation or recycling of the autolysosome is impaired. These results establish a role for PI(3,5)P-2 in autophagy in the mammalian central nervous system (CNS) and demonstrate that mutations affecting PI(3,5)P-2 can contribute to inclusion body disease.