2. Academic Validation
  3. Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis

Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis

  • Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):2935-41. doi: 10.1073/pnas.1501364112.
Yiguo Shen 1,  Woo-Ping Ge 2,  Yulong Li 3,  Arisa Hirano 1,  Hsien-Yang Lee 1,  Astrid Rohlmann 4,  Markus Missler 4,  Richard W Tsien 3,  Lily Yeh Jan 5,  Ying-Hui Fu 6,  Louis J Ptáček 7
Affiliations

Affiliations

  • 1 Department of Neurology.
  • 2 Department of Physiology, and.
  • 3 Department of Cellular & Molecular Physiology, Stanford University, Palo Alto, CA 94304; and.
  • 4 Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University & Cluster of Excellence EXC 1003, Cells in Motion, D-48149 Münster, Germany.
  • 5 Department of Physiology, and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158;
  • 6 Department of Neurology, ying-hui.fu@ucsf.edu ljp@ucsf.edu.
  • 7 Department of Neurology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94158; ying-hui.fu@ucsf.edu ljp@ucsf.edu.
PMID: 25730884 DOI: 10.1073/pnas.1501364112
Abstract

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.

Keywords

exocytosis; neurological disease; paroxysmal dyskinesia.

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