Pathological a-Syn exhibits in nerve terminals in DET and EUS of patients with MSA Propagation of pathological a-Syn from urinary tract to CNS causes MSA-like syndrome The mouse models show urinary dysfunction and abnormal EAS EMG before motor deficits Lower urinary tract injection of a-Syn PFFs induces autonomic and motor dysfunctions

35Multiple system atrophy (MSA) is a fatal adult-onset movement disorder with autonomic failures, 36 especially urogenital dysfunction. The neuropathological feature of MSA is the accumulation of 37 misfolded α-synuclein (α-Syn) in the nervous system. Here, we show that misfolded α-Syn exist 38 in nerve terminals in detrusor (DET) and external urethral sphincter (EUS) of patients with MSA. 39 Moreover, α-Syn preformed fibrils inoculated into the EUS or DET in TgM83 +/mice initiated the 40 transmission of misfolded α-Syn from the lower urinary tract to brain, and these mice developed 41 α-Syn inclusion pathology through micturition reflex pathways along with urinary dysfunction and 42 motor impairments. These findings indicate that spreading of misfolded α-Syn from the autonomic 43 control of the lower urinary tract to the brain via micturition reflex pathways induces autonomic 44 failure and motor impairments. These results provide important new insights into the pathogenesis 45 of MSA as well as highlight potential targets for early detection and therapeutics. 46 47 50 According to the most recent guidelines, autonomic failures featuring urogenital dysfunction, 51 orthostatic hypotension, and respiratory disorder are premonitory symptoms and necessary for 52