Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 10, Pages 2935-2941Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1501364112
Keywords
paroxysmal dyskinesia; exocytosis; neurological disease
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Funding
- NIH [U54 RR19481]
- Bachmann-Strauss Dystonia & Parkinson Foundation
- Sandler Neurogenetics Fund
- Dystonia Medical Research Foundation
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Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder precipitated by coffee, alcohol, and stress. We previously identified the causative gene but the function of the encoded protein remains unknown. We also generated a PNKD mouse model that revealed dysregulated dopamine signaling in vivo. Here, we show that PNKD interacts with synaptic active zone proteins Rab3-interacting molecule (RIM) 1 and RIM2, localizes to synapses, and modulates neurotransmitter release. Overexpressed PNKD protein suppresses release, and mutant PNKD protein is less effective than wild-type at inhibiting exocytosis. In PNKD KO mice, RIM1/2 protein levels are reduced and synaptic strength is impaired. Thus, PNKD is a novel synaptic protein with a regulatory role in neurotransmitter release.
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