Complex proteinopathies and neurodegeneration: insights from the study of transmissible spongiform encephalopathies

ABSTRACT Protein misfolding diseases are usually associated with deposits of single “key” proteins that somehow drive the pathology; β-amyloid and hyperphosphorylated tau accumulate in Alzheimer's disease, α-synuclein in Parkinson's disease, or abnormal prion protein (PrPTSE) in transmissible spongiform encephalopathies (TSEs or prion diseases). However, in some diseases more than two proteins accumulate in the same brain. These diseases might be considered “complex” proteinopathies. We have studied models of TSEs (to explore deposits of PrPTSE and of “secondary proteins”) infecting different strains and doses of TSE agent, factors that control incubation period, duration of illness and histopathology. Model TSEs allowed us to investigate whether different features of histopathology are independent of PrPTSE or appear as a secondary result of PrPTSE. Better understanding the complex proteinopathies may help to explain the wide spectrum of degenerative diseases and why some overlap clinically and histopathologically. These studies might also improve diagnosis and eventually even suggest new treatments for human neurodegenerative diseases.

摘要 蛋白质错误折叠疾病通常与单一"关键"蛋白质的沉积相关，这类蛋白质会以某种方式驱动病理进程：阿尔茨海默病中会积累β-淀粉样蛋白（β-amyloid）与过度磷酸化tau蛋白，帕金森病中会积累α-突触核蛋白（α-synuclein），而传染性海绵状脑病（TSEs或称朊蛋白病）中则会出现异常朊蛋白（PrPTSE）。然而在部分疾病中，会有两种以上的蛋白质在同一脑内沉积，这类疾病可被归类为"复杂性蛋白病（proteinopathies）"。本研究针对传染性海绵状脑病模型展开研究，以探究PrPTSE与"次级蛋白"的沉积情况；实验中使用了不同毒株与剂量的朊毒体因子，以此分析调控疾病潜伏期、病程时长与组织病理学特征的相关因素。此类模型可帮助我们探究：组织病理学的不同特征是否独立于PrPTSE，亦或是作为PrPTSE沉积的继发结果出现。对复杂性蛋白病的深入认知，有助于阐释退行性疾病的多样谱型，以及为何部分疾病在临床与组织病理学表现上存在重叠。此类研究或可提升人类神经退行性疾病的诊断水平，并最终为其提供全新的治疗策略。