Spread of pathological α-synuclein from urogenital nerves initiates multiple
2 system atrophy-like symptoms.
2019.
529594.full.pdf.
Abstract
.
36 Multiple system atrophy (MSA) is a fatal adult-onset movement disorder with autonomic failures,
37 especially urogenital dysfunction.
The neuropathological feature of MSA is the accumulation of
38 misfolded α-synuclein (α-Syn) in the nervous system. Here, we show that misfolded α-Syn exist
39 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 40 +/- mice initiated the
41 transmission of misfolded α-Syn from the lower urinary tract to brain, and these mice developed
42 α-Syn inclusion pathology through micturition reflex pathways along with urinary dysfunction and
43 motor impairments.
These findings indicate that spreading of misfolded α-Syn from the autonomic
44 control of the lower urinary tract to the brain via micturition reflex pathways induces autonomic
45 failure and motor impairments. These results provide important new insights into the pathogenesis
46 of MSA as well as highlight potential targets for early detection and therapeutics.