PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins

Hall, Emma A. and Nahorski, Michael S. and Murray, Lyndsay M. and Shaheen, Ranad and Perkins, Emma and Dissanayake, Kosala N. and Kristaryanto, Yosua and Jones, Ross A. and Vogt, Julie and Rivagorda, Manon and Handley, Mark T. and Mali, Girish R. and Quidwai, Tooba and Soares, Dinesh C. and Keighren, Margaret A. and McKie, Lisa and Mort, Richard L. and Gammoh, Noor and Garcia-Munoz, Amaya and Davey, Tracey and Vermeren, Matthieu and Walsh, Diana and Budd, Peter and Aligianis, Irene A. and Faqeih, Eissa and Quigley, Alan J. and Jackson, Ian J. and Kulathu, Yogesh and Jackson, Mandy and Ribchester, Richard R. and von Kriegsheim, Alex and Alkuraya, Fowzan S. and Woods, C. Geoffrey and Maher, Eamonn R. and Mill, Pleasantine (2017) PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins. American Journal of Human Genetics, 100 (5). pp. 706-724. ISSN 0002-9297

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Abstract

During neurotransmission, synaptic vesicles undergo multiple rounds of exo-endocytosis, involving recycling and/or degradation of synaptic proteins. While ubiquitin signaling at synapses is essential for neural function, it has been assumed that synaptic proteostasis requires the ubiquitin-proteasome system (UPS). We demonstrate here that turnover of synaptic membrane proteins via the endolysosomal pathway is essential for synaptic function. In both human and mouse, hypomorphic mutations in the ubiquitin adaptor protein PLAA cause an infantile-lethal neurodysfunction syndrome with seizures. Resulting from perturbed endolysosomal degradation, Plaa mutant neurons accumulate K63-polyubiquitylated proteins and synaptic membrane proteins, disrupting synaptic vesicle recycling and neurotransmission. Through characterization of this neurological intracellular trafficking disorder, we establish the importance of ubiquitin-mediated endolysosomal trafficking at the synapse.

Item Type:
Journal Article
Journal or Publication Title:
American Journal of Human Genetics
Additional Information:
Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2700/2716
Subjects:
ID Code:
86660
Deposited By:
Deposited On:
09 Jun 2017 15:00
Refereed?:
Yes
Published?:
Published
Last Modified:
09 Sep 2020 04:10