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

Autor:	Hall EA; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Nahorski MS; Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, UK; Department of Medical Genetics, University of Cambridge, and Cambridge NIHR Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge CB2 OXY, UK., Murray LM; Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK; Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh EH16 4SB, UK., Shaheen R; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia., Perkins E; Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK; Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh EH16 4SB, UK., Dissanayake KN; Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh EH16 4SB, UK; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK; Centre for Cognitive and Neural Systems, University of Edinburgh, Edinburgh EH8 9JZ, UK., Kristaryanto Y; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, UK., Jones RA; Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK; Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh EH16 4SB, UK., Vogt J; West Midlands Regional Genetics Service, Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham B15 2TG, UK., Rivagorda M; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Handley MT; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Mali GR; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Quidwai T; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Soares DC; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Keighren MA; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., McKie L; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Mort RL; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Gammoh N; Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Garcia-Munoz A; Systems Biology Ireland, University College Dublin, Dublin, Ireland., Davey T; Electron Microscopy Research Services, Newcastle University, Newcastle NE2 4HH, UK., Vermeren M; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Walsh D; West Midlands Regional Genetics Service, Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham B15 2TG, UK., Budd P; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Aligianis IA; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Faqeih E; Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh 11211, Saudi Arabia., Quigley AJ; NHS Lothian, Department of Paediatric Radiology, Royal Hospital for Sick Children, Edinburgh EH9 1LF, UK., Jackson IJ; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Kulathu Y; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, UK., Jackson M; Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK; Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh EH16 4SB, UK., Ribchester RR; Euan McDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh EH16 4SB, UK; Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK; Centre for Cognitive and Neural Systems, University of Edinburgh, Edinburgh EH8 9JZ, UK., von Kriegsheim A; Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; Systems Biology Ireland, University College Dublin, Dublin, Ireland., Alkuraya FS; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia., Woods CG; Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, UK; Department of Medical Genetics, University of Cambridge, and Cambridge NIHR Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge CB2 OXY, UK., Maher ER; Department of Medical Genetics, University of Cambridge, and Cambridge NIHR Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge CB2 OXY, UK. Electronic address: erm1000@medschl.cam.ac.uk., Mill P; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address: pleasantine.mill@igmm.ed.ac.uk.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2017 May 04; Vol. 100 (5), pp. 706-724. Date of Electronic Publication: 2017 Apr 13.
DOI:	10.1016/j.ajhg.2017.03.008
Abstrakt:	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. (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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