Roles of ESCRT in autophagy-associated neurodegeneration
Roles of ESCRT in autophagy-associated neurodegeneration
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DOI：
10.4161/auto.5384
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发表时间：
2008-02-16
期刊：
影响因子：
13.3
通讯作者：
Gao, Fen-Biao
中科院分区：
文献类型：
--
作者：
Lee, Jin-A;Gao, Fen-Biao
自噬是细胞质内容物和细胞器大量降解的调节途径，是包括神经系统在内的多个器官的许多生理和病理过程中的一个重要过程。有人提出，发育中的自噬小体在与溶酶体融合之前与晚期的内吞体室融合；然而，关于自噬和内吞途径之间的功能关系却知之甚少。在内体-溶酶体途径中，跨膜货物蛋白分选的关键步骤是由被称为ESCRT(运输所需的内体分选复合体)的多聚体复合体调控的。我们最近报道，ESCRT-III的功能障碍，无论是由于其基本亚基mSnf7-2的耗尽，还是通过与3号染色体相关的额颞部痴呆相关的突变CHMP2B蛋白的表达，在培养的成熟皮质神经元中，在神经退化之前，导致自噬小体积累和树突回缩。这一缺陷很可能是自噬小体与内小体隔室或溶酶体之间的异常融合过程的结果。这项研究表明，自噬途径后期步骤的缺陷可能与FTD和潜在的其他神经退行性疾病的发病机制有关。
Autophagy is a regulated pathway for bulk degradation of cytoplasmic contents and organelles, an important process involved in many physiological and pathological conditions in multiple organs, including the nervous system. It has been proposed that developing autophagosomes fuse with late endosomal compartments before their fusion with lysosomes; however, little is known about the functional relationship between the autophagy and endocytic pathways. In the endosomal-lysosomal pathway, a key step in sorting transmembrane cargo proteins is regulated by multimeric complexes called ESCRT (endosomal sorting complex required for transport). We recently reported that dysfunction of ESCRT-III, either by depletion of its essential subunit mSnf7-2 or by expression of a mutant CHMP2B protein associated with frontotemporal dementia linked to chromosome 3 (FTD3), caused autophagosome accumulation and dendritic retraction before neurodegeneration in cultured mature cortical neurons. This defect is likely a result of an abnormal fusion process between autophagosomes and endosomal compartments or lysosomes. This study suggests that defects in the late steps of the autophagy pathway may contribute to the pathogenesis of FTD and potentially other neurodegenerative diseases.