Ravikumar Brinda, Acevedo-Arozena Abraham, Imarisio Sara, Berger Zdenek, Vacher Coralie, O'Kane Cahir J, Brown Steve D M, Rubinsztein David C
Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, UK.
Nat Genet. 2005 Jul;37(7):771-6. doi: 10.1038/ng1591. Epub 2005 Jun 26.
Mutations that affect the dynein motor machinery are sufficient to cause motor neuron disease. It is not known why there are aggregates or inclusions in affected tissues in mice with such mutations and in most forms of human motor neuron disease. Here we identify a new mechanism of inclusion formation by showing that decreased dynein function impairs autophagic clearance of aggregate-prone proteins. We show that mutations of the dynein machinery enhanced the toxicity of the mutation that causes Huntington disease in fly and mouse models. Furthermore, loss of dynein function resulted in premature aggregate formation by mutant huntingtin and increased levels of the autophagosome marker LC3-II in both cell culture and mouse models, compatible with impaired autophagosome-lysosome fusion.
影响动力蛋白运动机制的突变足以导致运动神经元疾病。目前尚不清楚为何在患有此类突变的小鼠以及大多数人类运动神经元疾病形式中，受影响的组织会出现聚集体或包涵体。在此，我们通过表明动力蛋白功能下降会损害易聚集蛋白的自噬清除，从而确定了包涵体形成的一种新机制。我们发现，在果蝇和小鼠模型中，动力蛋白机制的突变增强了导致亨廷顿病的突变的毒性。此外，在细胞培养和小鼠模型中，动力蛋白功能丧失均导致突变型亨廷顿蛋白过早形成聚集体，并使自噬体标志物LC3-II水平升高，这与自噬体-溶酶体融合受损相一致。
