PT  - JOURNAL ARTICLE
AU  - Wei-Hua Chiu
AU  - Lora Kovacheva
AU  - Ruth E. Musgrove
AU  - Hadar Arien-Zakay
AU  - James B. Koprich
AU  - Jonathan M. Brotchie
AU  - Rami Yaka
AU  - Danny Ben-Zvi
AU  - Menachem Hanani
AU  - Jochen Roeper
AU  - Joshua A. Goldberg
TI  - α-Synuclein-induced Kv4 channelopathy in mouse vagal motoneurons causes non-motor parkinsonian symptoms
AID  - 10.1101/856070
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 856070
4099  - http://biorxiv.org/content/early/2019/11/26/856070.short
4100  - http://biorxiv.org/content/early/2019/11/26/856070.full
AB  - No disease modifying therapy is currently available for Parkinson’s disease (PD), the second most common neurodegenerative disease. The long non-motor 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 developing 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 and alters cardiac function – both clinically relevant symptoms of prodromal PD. We show for the first time a causal chain of events from α-synuclein via a biophysical dysfunction of specific neuronal populations to clinically relevant prodromal symptoms. These findings can facilitate the rational design of clinical biomarkers to identify people at risk for PD.