Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder
Noa Lipstein, … , Judith J. Jans, Nils Brose
Noa Lipstein, … , Judith J. Jans, Nils Brose
Published February 13, 2017
Citation Information: J Clin Invest. 2017;127(3):1005-1018. https://doi.org/10.1172/JCI90259.
View: Text | PDF
Research Article Neuroscience

Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder

Abstract

Munc13 proteins are essential regulators of neurotransmitter release at nerve cell synapses. They mediate the priming step that renders synaptic vesicles fusion-competent, and their genetic elimination causes a complete block of synaptic transmission. Here we have described a patient displaying a disorder characterized by a dyskinetic movement disorder, developmental delay, and autism. Using whole-exome sequencing, we have shown that this condition is associated with a rare, de novo Pro814Leu variant in the major human Munc13 paralog UNC13A (also known as Munc13-1). Electrophysiological studies in murine neuronal cultures and functional analyses in Caenorhabditis elegans revealed that the UNC13A variant causes a distinct dominant gain of function that is characterized by increased fusion propensity of synaptic vesicles, which leads to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity. Our study underscores the critical importance of fine-tuned presynaptic control in normal brain function. Further, it adds the neuronal Munc13 proteins and the synaptic vesicle priming process that they control to the known etiological mechanisms of psychiatric and neurological synaptopathies.

Authors

Noa Lipstein, Nanda M. Verhoeven-Duif, Francesco E. Michelassi, Nathaniel Calloway, Peter M. van Hasselt, Katarzyna Pienkowska, Gijs van Haaften, Mieke M. van Haelst, Ron van Empelen, Inge Cuppen, Heleen C. van Teeseling, Annemieke M.V. Evelein, Jacob A. Vorstman, Sven Thoms, Olaf Jahn, Karen J. Duran, Glen R. Monroe, Timothy A. Ryan, Holger Taschenberger, Jeremy S. Dittman, Jeong-Seop Rhee, Gepke Visser, Judith J. Jans, Nils Brose

×

Figure 5

Munc13-1P827L increases vesicular release probability by increasing SV fusogenicity.

Options: View larger image (or click on image) Download as PowerPoint
Munc13-1P827L increases vesicular release probability by increasing SV f...
(A and B) Autaptic hippocampal neurons were stimulated with hypertonic sucrose solution. The traces were integrated, normalized to the RRP size, aligned, and averaged. The average integrals for Munc13-1 Munc13-2 DKO neurons expressing Munc13-1WT (black) or Munc13-1P827L (red) stimulated by 500 mM sucrose (A) and by 250 mM sucrose (B) are shown. The insets show example traces. (C) Average peak release rates in neurons expressing Munc13-1WT (black) or Munc13-1P827L (red) during the application of 500 mM sucrose (left, P > 0.05) or 250 mM sucrose (right, P < 0.05). Individual values per neuron are indicated as circles (black, Munc13-1WT; red, Munc13-1P827L); Mann-Whitney test. (D) Average postsynaptic charge in neurons expressing Munc13-1WT (black) or Munc13-1P827L (red) during the application of 500 mM (left, P > 0.05) or 250 mM (right, P < 0.05) sucrose; Mann-Whitney test. Individual values per neuron are indicated as circles (black, Munc13-1WT; red, Munc13-1P827L). (E) Average ratio of the postsynaptic charge triggered by the application of 250 mM sucrose divided by that triggered by 500 mM sucrose (see D). Individual values per neuron are indicated as circles (black, Munc13-1WT; red, Munc13-1P827L), P < 0.01; Mann-Whitney test. All error bars in the figure represent mean ± SEM. *P < 0.05, **P < 0.01; NS, P > 0.05. See Table 2 for further details.