Chaperone-mediated autophagy (CMA) is a substrate-specific mode of lysosomal proteolysis, with multiple lines of evidence connecting its dysfunction to both ageing and disease. We have recently shown that CMA impairment through knock-down of the lysosomal receptor LAMP2A is detrimental to neuronal viability in vivo; however, it is not clear which subset of proteins regulated by the CMA pathway mediate such changes. In this study, we have manipulated CMA function through alterations of LAMP2A abundance in primary rat cortical neurons, to identify potential changes to the neuronal proteome occurring prior to neurotoxic effects. We have identified a list of proteins with significant, >2-fold change in abundance following our manipulations, of which PARK7/DJ-1 - an anti-oxidant implicated in hereditary forms of Parkinson's Disease (PD), and DPYSL2/CRMP-2 - a microtubule-binding phosphoprotein involved in schizophrenia pathogenesis - were both found to have measurable effects on neuronal homeostasis and phenotype. Taken together, this study describes alterations in the abundance of neuronal proteins involved in neuropsychiatric disorders upon CMA manipulation, and suggests that such alterations may in part be responsible for the neurodegeneration observed upon CMA impairment in vivo.

中文翻译：

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伴侣蛋白介导的自噬的受损通过改变DJ-1和C​​RMP-2蛋白的表达影响神经元稳态。

伴侣蛋白介导的自噬（CMA）是溶酶体蛋白水解的特定底物模式，有多条证据将其功能障碍与衰老和疾病联系起来。我们最近发现，通过敲低溶酶体受体LAMP2A引起的CMA损害对体内神经元生存力有害。然而，尚不清楚由CMA途径调节的蛋白质的哪个子集介导这种变化。在这项研究中，我们已经通过改变原代大鼠皮层神经元中LAMP2A的丰度来操纵CMA功能，以识别在神经毒性作用发生之前神经元蛋白质组的潜在变化。我们已经确定了一系列蛋白质，这些蛋白质在我们的操作后的丰度发生了显着的> 2倍变化，其中PARK7 / DJ-1是一种抗氧化剂，与帕金森氏病（PD）的遗传形式有关，和DPYSL2 / CRMP-2（一种与精神分裂症发病机制有关的微管结合磷蛋白）均被发现对神经元稳态和表型具有可测量的作用。综上所述，这项研究描述了在CMA操作后涉及神经精神疾病的神经元蛋白丰富度的变化，并表明这种变化可能部分归因于体内CMA损伤时观察​​到的神经退行性变。