Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders.
Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders.
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DOI：
10.1002/ana.22615
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发表时间：
2011-10
影响因子：
11.2
通讯作者：
Walker, Lary C.
中科院分区：
文献类型：
--
作者：
Jucker, Mathias;Walker, Lary C.
特定蛋白质的错误折叠和聚集是各种神经退行性疾病中的一个开创性事件。在阿尔茨海默病（最普遍的脑蛋白质病）中，两种主要的聚集蛋白是β-淀粉样蛋白（Aβ）和tau。由这些蛋白质的构象变体形成的异常组装体的大小范围从小的寡聚体到通过光学显微镜可见的特征性病变，如老年斑和神经纤维缠结。与朊病毒病的病理学相似性表明，这些蛋白质性病变的形成和扩散可能涉及一个共同的分子机制-破坏性蛋白质模板。在实验中，暴露于含有聚集Aβ种子的稀释脑提取物可外源性诱导脑β淀粉样变性。淀粉样蛋白诱导剂可能是Aβ本身，在活体大脑中最有效地产生构象。一旦开始，Aβ病变在脑区域内和脑区域之间增殖。诱导过程受Aβ种子的结构和生化性质以及宿主的属性控制，这让人联想到致病性变异朊病毒株。朊病毒样诱导和致病蛋白扩散的概念最近已经扩展到包括tau、α-突触核蛋白、亨廷顿蛋白、超氧化物歧化酶-1和TDP-43的聚集体，其表征了诸如额颞叶变性、帕金森/路易体病、亨廷顿病和肌萎缩侧索硬化症等人类神经退行性疾病。我们最近发现，最有效的Aβ种子是小的和可溶的，这加强了在体液中寻找蛋白质级联反应上游的错误折叠蛋白质种子的研究，因此可以作为预测性诊断和早期基于机制的干预措施的目标。建立腐败蛋白质模板的临床意义将需要进一步的机制和流行病学调查。然而，许多慢性神经退行性疾病可以通过错误折叠蛋白质的种子腐败来起源和发展的理论有可能统一这些日益普遍的疾病的实验和转化方法。
The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer’s disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism – corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prion-like induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson’s/Lewy body disease, Huntington’s disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders.
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影响因子：
12.7
作者：
Braak, Heiko;Del Tredici, Kelly
通讯作者：
Del Tredici, Kelly
影响因子：
6
作者：
Bolmont, Tristan;Clavaguera, Florence;Jucker, Mathias
通讯作者：
Jucker, Mathias
影响因子：
2.6
作者：
Brown, Khalilah;Mastrianni, James A.
通讯作者：
Mastrianni, James A.
影响因子：
3
作者：
Crowther, RA;Goedert, M
通讯作者：
Goedert, M
DOI：
10.1073/pnas.0903200106
发表时间：
2009-08-04
影响因子：
11.1
作者：
Eisele, Yvonne S.;Bolmont, Tristan;Jucker, Mathias
通讯作者：
Jucker, Mathias