Xilouri Maria, Brekk Oeystein Roed, Polissidis Alexia, Chrysanthou-Piterou Margarita, Kloukina Ismini, Stefanis Leonidas
a Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens , Athens , Greece.
b University of Crete, School of Medicine , Heraklion , Crete , Greece.
Autophagy. 2016 Nov;12(11):2230-2247. doi: 10.1080/15548627.2016.1214777. Epub 2016 Aug 19.
Chaperone-mediated autophagy (CMA) involves the selective lysosomal degradation of cytosolic proteins such as SNCA (synuclein α), a protein strongly implicated in Parkinson disease (PD) pathogenesis. However, the physiological role of CMA and the consequences of CMA failure in the living brain remain elusive. Here we show that CMA inhibition in the adult rat substantia nigra via adeno-associated virus-mediated delivery of short hairpin RNAs targeting the LAMP2A receptor, involved in CMA's rate limiting step, was accompanied by intracellular accumulation of SNCA-positive puncta, which were also positive for UBIQUITIN, and in accumulation of autophagic vacuoles within LAMP2A-deficient nigral neurons. Strikingly, LAMP2A downregulation resulted in progressive loss of nigral dopaminergic neurons, severe reduction in striatal dopamine levels/terminals, increased astro- and microgliosis and relevant motor deficits. Thus, this study highlights for the first time the importance of the CMA pathway in the dopaminergic system and suggests that CMA impairment may underlie PD pathogenesis.
伴侣介导的自噬（CMA）涉及对胞质蛋白（如SNCA（α-突触核蛋白））的选择性溶酶体降解，SNCA是一种与帕金森病（PD）发病机制密切相关的蛋白质。然而，CMA的生理作用以及CMA功能障碍在活脑中的后果仍不清楚。在这里，我们表明，通过腺相关病毒介导的针对参与CMA限速步骤的LAMP2A受体的短发夹RNA的递送，在成年大鼠黑质中抑制CMA，伴随着SNCA阳性点状结构的细胞内积累，这些点状结构对泛素也呈阳性，并且在LAMP2A缺陷的黑质神经元内自噬泡积累。引人注目的是，LAMP2A下调导致黑质多巴胺能神经元逐渐丧失，纹状体多巴胺水平/终末严重降低，星形胶质细胞和小胶质细胞增生增加以及相关运动缺陷。因此，本研究首次强调了CMA途径在多巴胺能系统中的重要性，并表明CMA损伤可能是PD发病机制的基础。
