神经病理学研究进展讲述.pptx

神经退行性疾病分子病理学研究进展 孙秉贵 浙江大学神经科学研究所bsun@ /sunbg Oct. 12th, 2015 课程提纲 神经退行性疾病的病理变化 神经退行性疾病的致病因素及其机制 神经退行性疾病的研究进展 课程提纲 神经退行性疾病的病理变化 神经退行性疾病的致病因素及其机制 神经退行性疾病的研究进展 神经退行性疾病 神经退行性疾病（neurodegenerative diseases）是一类慢性、随着年龄增长而进行性加重的神经系统疾病，由神经退行性病变而引起。 Neurodegeneration is the term for the progressive loss of structure or function of neurons, including death of neurons. 常见神经退行性疾病 Nat Rev Neurosci 2003, 4:49-60 Protein deposition in the brain of different types of neurodegenerative diseases Cerebral aggregates in neurodegenerative diseases Nat Rev Neurosci 2003, 4:49-60 Extracellular amyloid plaques (white arrows) and intracytoplasmic neurofibrillary tangles (yellow arrows) are the pathological signature of Alzheimer’s disease. Intracytoplasmic aggregates are typically present in the neurons of people affected by Parkinson’s disease and amyotrophic lateral sclerosis. Intranuclear inclusions of huntingtin are observed in Huntington’s disease patients and extracellular prion amyloid plaques that are located in different brain regions are present in some cases of transmissible spongiform encephalopathy. In spite of the different protein compositions, the ultrastructure of these deposits seems to be similar and composed mainly of a network of fibrillar polymers (centre). 神经退行性疾病：蛋白质异常聚集 Nat Rev Neurosci 2003, 4:49-60 Abnormal Accumulation of Proteins in the Brain Is Dependent on Their Production and Clearance Cold Spring Harb Perspect Med 2012, 2(6):a006379 AβDP: Aβ-degrading protease UPS Autophagy Selkoe et al, 2001 Amyloid Precursor Protein (APP) and Its Processing 基因突变或过表达可导致相关蛋白生成增加 基因突变或过表达可导致相关蛋白生成增加 Selkoe et al, 2001 Amyloid Precursor Protein (APP) and Its Processing 蛋白质错误折叠与异常聚集 Nat Rev Neurosci 2003, 4:49-60 蛋白质折叠异常影响蛋白质的降解和清除 Soluble misfolded monomers and dimers can be recognized by both the UPS or CMA(chaperone-mediated autophagy)-related chaperones, and subsequently degraded by either of these two pathways. In the case of CMA, cytosoli