Spread of pathological α-synuclein from urogenital nerves initiates multiple system atrophy-like symptoms

Multiple system atrophy (MSA) is a fatal adult-onset movement disorder with autonomic failures, especially urogenital dysfunction. The neuropathological feature of MSA is the accumulation of misfolded α-synuclein (α-Syn) in the nervous system. Here, we show that misfolded α-Syn exist in nerve terminals in detrusor (DET) and external urethral sphincter (EUS) of patients with MSA. Moreover, α-Syn preformed fibrils inoculated into the EUS or DET in TgM83+/- mice initiated the transmission of misfolded α-Syn from the lower urinary tract to brain, and these mice developed α-Syn inclusion pathology through micturition reflex pathways along with urinary dysfunction and motor impairments. These findings indicate that spreading of misfolded α-Syn from the autonomic control of the lower urinary tract to the brain via micturition reflex pathways induces autonomic failure and motor impairments. These results provide important new insights into the pathogenesis of MSA as well as highlight potential targets for early detection and therapeutics.