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α-Synuclein-induced Kv4 channelopathy in mouse vagal motoneurons causes non-motor parkinsonian symptoms

View ORCID ProfileWei-Hua Chiu, Lora Kovacheva, Ruth E. Musgrove, Hadar Arien-Zakay, View ORCID ProfileJames B. Koprich, View ORCID ProfileJonathan M. Brotchie, View ORCID ProfileRami Yaka, View ORCID ProfileDanny Ben-Zvi, View ORCID ProfileMenachem Hanani, View ORCID ProfileJochen Roeper, View ORCID ProfileJoshua A. Goldberg
doi: https://doi.org/10.1101/856070
Wei-Hua Chiu
1Department of Medical Neurobiology, Institute of Medical Research Israel – Canada, The Faculty of Medicine, The Hebrew University of Jerusalem, 9112102 Jerusalem, Israel
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Lora Kovacheva
2Institute of Neurophysiology, Neuroscience Center, Goethe-University, 60590 Frankfurt, Germany
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Ruth E. Musgrove
1Department of Medical Neurobiology, Institute of Medical Research Israel – Canada, The Faculty of Medicine, The Hebrew University of Jerusalem, 9112102 Jerusalem, Israel
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Hadar Arien-Zakay
3School of Pharmacy, Institute for Drug Research, The Faculty of Medicine, The Hebrew University of Jerusalem, 9112102 Jerusalem, Israel
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James B. Koprich
4Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, M5T 2S8, Canada
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Jonathan M. Brotchie
4Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, M5T 2S8, Canada
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Rami Yaka
3School of Pharmacy, Institute for Drug Research, The Faculty of Medicine, The Hebrew University of Jerusalem, 9112102 Jerusalem, Israel
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Danny Ben-Zvi
5Department of Developmental Biology and Cancer Research, Institute of Medical Research Israel – Canada, The Faculty of Medicine, The Hebrew University of Jerusalem, 9112102 Jerusalem, Israel
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Menachem Hanani
6Laboratory of Experimental Surgery, Hadassah Medical Center, Mount Scopus, 91240 Jerusalem & The Faculty of Medicine, The Hebrew University of Jerusalem
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Jochen Roeper
2Institute of Neurophysiology, Neuroscience Center, Goethe-University, 60590 Frankfurt, Germany
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Joshua A. Goldberg
1Department of Medical Neurobiology, Institute of Medical Research Israel – Canada, The Faculty of Medicine, The Hebrew University of Jerusalem, 9112102 Jerusalem, Israel
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  • For correspondence: joshua.goldberg2@mail.huji.ac.il
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Summary

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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 26, 2019.
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α-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
bioRxiv 856070; doi: https://doi.org/10.1101/856070
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α-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
bioRxiv 856070; doi: https://doi.org/10.1101/856070

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