Alpha-Synuclein-induced Kv4 channelopathy in mouse vagal motoneurons causes non-motor 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

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Dec 13, 2019
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Received Date: 1st December 19

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 alpha-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 vitroand 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 alpha-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.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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