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.

路易体疾病是一种异质性神经系统疾病，其定义为由畸形 α-突触核蛋白聚集体组成的细胞内包涵体。尽管 α-突触核蛋白聚集体只是内含物的一种组成部分，并且与神经变性并不严格相关，但有证据表明它们在细胞内和细胞间传播路易病理学。编码 α-突触核蛋白的基因的基因突变、基因组倍增和序列多态性也与路易体病有因果关系。在路易体病的非家族性病例中，疾病触发因素仍未确定，但范围可能从工业/农业毒物和天然毒物来源到微生物病原体。也许由于这些外周暴露，路易包涵体出现在疾病早期阶段与颅神经 I 和 X 相连的大脑区域，这些神经与鼻腔或胃肠腔中吸入和摄入的环境元素相互作用。无论其身份如何，隐秘的疾病触发因素很可能将可溶性 α-突触核蛋白（直接或间接）转变为不溶性的跨 β 片层聚集物。事实上，富含 β-折叠的自我复制 α-突触核蛋白多聚体存在于患者血浆、脑脊液和其他组织中，并且可以进行 α-突触核蛋白种子扩增测定。因此，在未来 α-突触核蛋白靶向治疗的临床试验中，临床医生应该能够利用 α-突触核蛋白种子扩增测定将患者分为潜在应答者和无应答者。在这里，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-突触核蛋白病跨神经轴潜在传播的病理生理过程。