ABSTRACT

The macroautophagy/autophagy-lysosome axis enables the clearance and degradation of cytoplasmic components including protein aggregates, damaged organelles and invading pathogens. Protein aggregation and lysosomal system dysfunction in the brain are common features of several late-onset neurological disorders including Alzheimer disease. Spatial overlap between depletion of the endosomal-sorting complex retromer and MAPT/tau aggregation in the brain have been previously reported. However, whether retromer dysfunction plays a direct role in mediating MAPT aggregation remains unclear. Here, we demonstrate that the autophagy-lysosome axis is the primary mode for the clearance of aggregated species of MAPT using both chemical and genetic approaches in cell models of amyloid MAPT aggregation. We show that depletion of the central retromer component VPS35 causes a block in the resolution of autophagy. We establish that this defect underlies marked accumulation of cytoplasmic MAPT aggregates upon VPS35 depletion, and that VPS35 overexpression has the opposite effect. This work illustrates how retromer complex integrity regulates the autophagy-lysosome axis to suppress MAPT aggregation and spread.

摘要

巨自噬/自噬-溶酶体轴能够清除和降解细胞质成分，包括蛋白质聚集体、受损细胞器和入侵病原体。大脑中的蛋白质聚集和溶酶体系统功能障碍是包括阿尔茨海默病在内的几种迟发性神经系统疾病的共同特征。先前已经报道了内体分选复合物逆转录酶的消耗和大脑中的 MAPT/tau 聚集之间的空间重叠。然而，逆转录酶功能障碍是否在介导 MAPT 聚集中起直接作用仍不清楚。在这里，我们证明自噬-溶酶体轴是在淀粉样蛋白 MAPT 聚集的细胞模型中使用化学和遗传方法清除 MAPT 聚集物种的主要模式。我们表明，中央逆转录酶成分 VPS35 的消耗会导致自噬的解决受阻。我们确定这种缺陷是 VPS35 耗尽后细胞质 MAPT 聚集体显着积累的基础，并且 VPS35 过表达具有相反的效果。这项工作说明了逆转录酶复合物的完整性如何调节自噬-溶酶体轴以抑制 MAPT 聚集和扩散。