Moreau Kevin, Fleming Angeleen, Imarisio Sara, Lopez Ramirez Ana, Mercer Jacob L, Jimenez-Sanchez Maria, Bento Carla F, Puri Claudia, Zavodszky Eszter, Siddiqi Farah, Lavau Catherine P, Betton Maureen, O'Kane Cahir J, Wechsler Daniel S, Rubinsztein David C
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
1] Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK [2] Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
Nat Commun. 2014 Sep 22;5:4998. doi: 10.1038/ncomms5998.
Genome-wide association studies have identified several loci associated with Alzheimer's disease (AD), including proteins involved in endocytic trafficking such as PICALM/CALM (phosphatidylinositol binding clathrin assembly protein). It is unclear how these loci may contribute to AD pathology. Here we show that CALM modulates autophagy and alters clearance of tau, a protein which is a known autophagy substrate and which is causatively linked to AD, both in vitro and in vivo. Furthermore, altered CALM expression exacerbates tau-mediated toxicity in zebrafish transgenic models. CALM influences autophagy by regulating the endocytosis of SNAREs, such as VAMP2, VAMP3 and VAMP8, which have diverse effects on different stages of the autophagy pathway, from autophagosome formation to autophagosome degradation. This study suggests that the AD genetic risk factor CALM modulates autophagy, and this may affect disease in a number of ways including modulation of tau turnover.
全基因组关联研究已经确定了几个与阿尔茨海默病（AD）相关的基因座，包括参与内吞运输的蛋白质，如PICALM/CALM（磷脂酰肌醇结合网格蛋白组装蛋白）。目前尚不清楚这些基因座如何导致AD病理变化。在这里，我们表明CALM在体外和体内均能调节自噬并改变tau蛋白的清除，tau蛋白是一种已知的自噬底物，与AD存在因果关系。此外，在斑马鱼转基因模型中，CALM表达的改变会加剧tau介导的毒性。CALM通过调节SNARE蛋白（如VAMP2、VAMP3和VAMP8）的内吞作用来影响自噬，这些蛋白对自噬途径的不同阶段（从自噬体形成到自噬体降解）具有不同影响。这项研究表明，AD遗传风险因子CALM调节自噬，这可能会以多种方式影响疾病，包括调节tau蛋白的周转。
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