Rehana K. Leak, Rachel N. Clark, Muslim Abbas, Fei Xu, Jeffrey L. Brodsky, Jun Chen, Xiaoming Hu, Kelvin C. Luk
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引用次数: 0
Abstract
Lewy body disorders are heterogeneous neurological conditions defined by intracellular inclusions composed of misshapen α-synuclein protein aggregates. Although α-synuclein aggregates are only one component of inclusions and not strictly coupled to neurodegeneration, evidence suggests they seed the propagation of Lewy pathology within and across cells. Genetic mutations, genomic multiplications, and sequence polymorphisms of the gene encoding α-synuclein are also causally linked to Lewy body disease. In nonfamilial cases of Lewy body disease, the disease trigger remains unidentified but may range from industrial/agricultural toxicants and natural sources of poisons to microbial pathogens. Perhaps due to these peripheral exposures, Lewy inclusions appear at early disease stages in brain regions connected with cranial nerves I and X, which interface with inhaled and ingested environmental elements in the nasal or gastrointestinal cavities. Irrespective of its identity, a stealthy disease trigger most likely shifts soluble α-synuclein (directly or indirectly) into insoluble, cross-β-sheet aggregates. Indeed, β-sheet-rich self-replicating α-synuclein multimers reside in patient plasma, cerebrospinal fluid, and other tissues, and can be subjected to α-synuclein seed amplification assays. Thus, clinicians should be able to capitalize on α-synuclein seed amplification assays to stratify patients into potential responders versus non-responders in future clinical trials of α-synuclein targeted therapies. Here, we briefly review the current understanding of α-synuclein in Lewy body disease and speculate on pathophysiological processes underlying the potential transmission of α-synucleinopathy across the neuraxis.
路易体疾病是一种由畸形的α-突触核蛋白聚集体构成的细胞内包涵体所定义的神经系统疾病。虽然α-突触核蛋白聚集体只是内含物的一个组成部分,与神经变性并无严格关联,但有证据表明,它们是路易体病理学在细胞内和细胞间传播的种子。α-突触核蛋白编码基因的基因突变、基因组增殖和序列多态性也与路易体疾病有因果关系。在路易体病的非家族病例中,疾病的诱因仍未确定,但可能包括工业/农业毒物、天然毒物来源和微生物病原体。也许是由于这些外周接触,路易包涵体在疾病早期出现在与颅神经 I 和 X 相连的脑区,这些脑区与鼻腔或胃肠道中吸入和摄入的环境因素相接。无论其身份如何,隐性疾病诱因最有可能(直接或间接)将可溶的α-突触核蛋白转变为不溶的、交叉β片状聚集体。事实上,患者血浆、脑脊液和其他组织中都存在富含β片的自我复制α-突触核蛋白多聚体,并可进行α-突触核蛋白种子扩增试验。因此,在未来的α-突触核蛋白靶向疗法临床试验中,临床医生应能利用α-突触核蛋白种子扩增检测将患者分为潜在应答者和非应答者。在此,我们简要回顾了目前对路易体病中α-突触核蛋白的认识,并推测了α-突触核蛋白病可能在神经轴中传播的病理生理过程。
期刊介绍:
Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.