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

Sci Adv. 2021 Mar 10;7(11):eabd3994. doi: 10.1126/sciadv.abd3994. Print 2021 Mar.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Channelopathies*
  • Humans
  • Mice
  • Motor Neurons
  • Neurodegenerative Diseases*
  • Parkinson Disease* / etiology
  • alpha-Synuclein / genetics

Substances

  • alpha-Synuclein