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

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

doi:10.1016/j.isci.2020.101166

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

iScience. 2020 Jun 26;23(6):101166. doi: 10.1016/j.isci.2020.101166. Epub 2020 May 15.

Authors

Xuebing Ding¹, Lebo Zhou², Xiaoyi Jiang², Han Liu², Jing Yao², Rui Zhang², Dongxiao Liang², Fengfei Wang³, Mingming Ma⁴, Beisha Tang⁵, Erxi Wu⁶, Junfang Teng⁷, Xuejing Wang⁸

Affiliations

¹ Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Henan 450052, China. Electronic address: fccdingxb@zzu.edu.cn.
² Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Henan 450052, China.
³ Neuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, TX 76508, USA; College of Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA.
⁴ Department of Neurology, Affiliated People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China. Electronic address: macklon12@zzu.edu.cn.
⁵ Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, China. Electronic address: bstang7398@163.com.
⁶ Neuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, TX 76508, USA; College of Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA; College of Pharmacy, Texas A&M Health Science Center, College Station, TX 77843, USA; LIVESTRONG Cancer Institutes, Dell Medical School, the University of Texas at Austin, Austin, TX 78712, USA. Electronic address: erxi.wu@bswhealth.org.
⁷ Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Henan 450052, China. Electronic address: 13838210077@163.com.
⁸ Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Henan 450052, China. Electronic address: fccwangxj2@zzu.edu.cn.

Abstract

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.

Keywords: Behavioral Neuroscience; Biological Sciences; Neuroscience.