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152637 - Alpha-Synuclein-induced Kv4 channelopathy in mouse vagal motoneurons drives nonmotor parkinsonian symptoms.pdf (3.96 MB)

Alpha-Synuclein-induced Kv4 channelopathy in mouse vagal motoneurons drives nonmotor parkinsonian symptoms

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posted on 2023-05-21, 12:30 authored by Chiu, WH, Kovacheva, L, Ruth MusgroveRuth Musgrove, Arien-Zakay, H, Koprich, JB, Brotchie, J, Yaka, R, Ben-Zvi, D, Hanani, M, Roeper, J, Goldberg, JA
No disease-modifying therapy is currently available for Parkinson's disease (PD), the second most common neurodegenerative disease. The long nonmotor prodromal phase of PD is a window of opportunity for early detection and intervention. However, we lack the pathophysiological understanding to develop selective biomarkers and interventions. By using a mutant a-synuclein selective-overexpression mouse model of prodromal PD, we identified a cell-autonomous selective Kv4 channelopathy in dorsal motor nucleus of the vagus (DMV) neurons. This functional remodeling of intact DMV neurons leads to impaired pacemaker function in vitro and in vivo, which, in turn, reduces gastrointestinal motility, a common early symptom of prodromal PD. We identify a chain of events from a-synuclein via a biophysical dysfunction of a specific neuronal population to a clinically relevant prodromal symptom. These findings will facilitate the rational design of clinical biomarkers to identify people at risk for developing PD.

History

Publication title

Science Advances

Volume

7

Issue

11

Article number

eabd3994

Number

eabd3994

ISSN

2375-2548

Department/School

Menzies Institute for Medical Research

Publisher

American Association for the Advancement of Science (AAAS)

Place of publication

United States

Rights statement

Copyright 2021 The Authors Licensed under Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) https://creativecommons.org/licenses/by-nc/4.0/

Repository Status

  • Open

Socio-economic Objectives

Clinical health not elsewhere classified

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