selective molecular alterations in the autophagy pathway in patients with lewy body disease and in models of α-synucleinopathy选择性自噬通路中的分子改变患者的路易α-synucleinopathy的身体疾病和模型.pdfVIP

Selective Molecular Alterations in the Autophagy Pathway in Patients with Lewy Body Disease and in Models of a-Synucleinopathy 1 2 2 2 2 2 Leslie Crews , Brian Spencer , Paula Desplats , Christina Patrick , Amy Paulino , Edward Rockenstein , 1,2 2 2 1,2 Lawrence Hansen , Anthony Adame , Douglas Galasko , Eliezer Masliah * 1 Department of Pathology, University of California San Diego, La Jolla, California, United States of America, 2 Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America Abstract Background: Lewy body disease is a heterogeneous group of neurodegenerative disorders characterized by a-synuclein accumulation that includes dementia with Lewy bodies (DLB) and Parkinson’s Disease (PD). Recent evidence suggests that impairment of lysosomal pathways (i.e. autophagy) involved in a-synuclein clearance might play an important role. For this reason, we sought to examine the expression levels of members of the autophagy pathway in brains of patients with DLB and Alzheimer’s Disease (AD) and in a-synuclein transgenic mice. Methodology/Principal Findings: By immunoblot analysis, compared to controls and AD, in DLB cases levels of mTor were elevated and Atg7 were reduced. Levels of other components of the autophagy pathway such as Atg5, Atg10, Atg12 and Beclin-1 were not different in DLB compared to controls. In DLB brains, mTor was more abundant in neurons displaying a- synuclein accumulation. These neurons also showed abnormal expression of lysosomal markers such as LC3, and ultrastructural anal