The downward spiral of tau and autolysosomes: a new hypothesis in neurodegeneration.
The downward spiral of tau and autolysosomes: a new hypothesis in neurodegeneration.
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DOI：
10.4161/auto.20515
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发表时间：
2012-07-01
期刊：
影响因子：
13.3
通讯作者：
Jackson GR
中科院分区：
文献类型：
--
作者：
Ambegaokar SS;Jackson GR
越来越多的研究将自噬与阿尔茨海默病（AD）等神经退行性疾病联系起来。在尸检的AD脑中，大的多泡体聚集在神经元中。缺乏关键自噬基因的敲除小鼠表现出年龄依赖性神经变性。大多数神经退行性疾病的特征在于不溶性蛋白质种类的积累;蛋白质的类型和聚集体在神经系统内的位置有助于确定疾病的类型。据推测，不能降解这种聚集体是神经元功能障碍和最终神经元死亡的主要致病因素。由于神经元是有丝分裂后的，因此不能自我再生，因此蛋白质清除机制在该领域受到了广泛关注。泛素-蛋白酶体系统（UPS）的功能在神经变性模型中受损，并且伴侣蛋白（例如HSP 70家族中的那些）的过表达在许多蛋白质病模型中导致有益作用。最近，关于自噬作为清除机制的作用的研究已经发现了令人信服的证据，即诱导自噬可以减轻神经变性的动物和细胞模型中的许多致病性和行为症状。
A growing body of research has connected autophagy to neurodegenerative diseases such as Alzheimer disease (AD). In autopsied AD brain, large multivesicular bodies accumulate in neurons. Knockout mice deficient for key autophagy genes demonstrate age-dependent neurodegeneration. Most neurodegenerative diseases are characterized by accumulation of insoluble protein species; the type of protein and the location of aggregates within the nervous system help to define the type of disorder. It has been hypothesized that the inability to degrade such aggregates is a major causative factor in neuronal dysfunction and eventual neuronal death. As neurons are postmitotic and thus cannot regenerate themselves, mechanisms of protein clearance have received much attention in the field. The function of the ubiquitin-proteasome system (UPS) is impaired in models of neurodegeneration, and overexpression of chaperone proteins, such as those in the HSP70 family, leads to beneficial effects in many models of proteinopathies. Recently, studies of the effects of autophagy as a clearance mechanism have uncovered compelling evidence that inducing autophagy can alleviate many pathogenic and behavioral symptoms in animal and cellular models of neurodegeneration.