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

Emma A. Hall, Michael S. Nahorski, Lyndsay M. Murray, Ranad Shaheen, Emma Perkins, Kosala N. Dissanayake, Yosua Kristaryanto, Ross A. Jones, Julie Vogt, Manon Rivagorda, Mark T. Handley, Girish R. Mali, Tooba Quidwai, Dinesh C. Soares, Margaret A. Keighren, Lisa McKie, Richard L. Mort, Noor Gammoh, Amaya Garcia-Munoz, Tracey DaveyMatthieu Vermeren, Diana Walsh, Peter Budd, Irene A. Aligianis, Eissa Faqeih, Alan J. Quigley, Ian J. Jackson, Yogesh Kulathu, Mandy Jackson, Richard R. Ribchester, Alex von Kriegsheim, Fowzan S. Alkuraya, C. Geoffrey Woods, Eamonn R. Maher, Pleasantine Mill

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)706-724
JournalAmerican Journal of Human Genetics
Volume100
Issue number5
Early online date13 Apr 2017
DOIs
Publication statusPublished - 4 May 2017

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