Open Accessα-Synuclein–induced Kv4 channelopathy in mouse vagal motoneurons drives nonmotor parkinsonian symptoms
Author(s) -
WeiHua Chiu,
Lora Kovacheva,
Ruth E. Musgrove,
Hadar ArienZakay,
James B. Koprich,
Jonathan M. Brotchie,
Rami Yaka,
Danny BenZvi,
Menachem Hanani,
Jochen Roeper,
Joshua A. Goldberg
Publication year - 2021
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abd3994
Subject(s) - channelopathy , neuroscience , dorsal motor nucleus , parkinson's disease , disease , medicine , population , alpha synuclein , biology , vagus nerve , stimulation , environmental health
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 α-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 α-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.