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

Wei Hua Chiu, Lora Kovacheva, Ruth E. Musgrove, Hadar Arien-Zakay, James B. Koprich, Jonathan M. Brotchie, Rami Yaka, Danny Ben-Zvi, Menachem Hanani, Jochen Roeper, Joshua A. Goldberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageAmerican English
Article numbereabd3994
JournalScience advances
Volume7
Issue number11
DOIs
StatePublished - Mar 2021

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