Propagation of Pathological α-Synuclein from the Urogenital Tract to the Brain Initiates MSA-like Syndrome

作者：Xuebing Ding, Lebo Zhou, Xiaoyi Jiang, Han Liu, Jing Yao, Rui Zhang, Dongxiao Liang, Fengfei Wang, Mingming Ma, Beisha Tang, Erxi Wu, Junfang Teng, Xuejing Wang · 发表于：iScience · 年份：2020 · DOI：10.1016/j.isci.2020.101166 · 被引用次数：34 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Botulinum Toxin and Related Neurological Disorders、Neurological diseases and metabolism

The neuropathological feature of multiple system atrophy (MSA), a fatal adult-onset disorder without effective therapy, is the accumulation of pathological α-synuclein (α-Syn) in the central nervous system (CNS). Here we show that pathological α-Syn exists in nerve terminals in detrusor and external urethral sphincter (EUS) of patients with MSA. Furthermore, α-Syn-preformed fibrils (PFFs) injected in the EUS or detrusor in TgM83 +/− mice initiated the transmission of pathological α-Syn from the urogenital tract to brain via micturition reflex pathways, and these mice developed widespread phosphorylated α-Syn inclusion pathology together with phenotypes. In addition, urinary dysfunction and denervation-reinnervation of external anal sphincter were detected earlier in the mouse models with α-Syn PFFs inoculation before the behavioral manifestations. These results suggest that pathological α-Syn spreading through the micturition reflex pathways retrogradely from the urogenital tract to CNS may lead to urinary dysfunction in patients with MSA, which is different from the etiology of idiopathic Parkinson disease.