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

Am J Hum Genet. 2017 May 4;100(5):706-724. doi: 10.1016/j.ajhg.2017.03.008.

Emma A Hall ¹, Michael S Nahorski ², Lyndsay M Murray ³, Ranad Shaheen ⁴, Emma Perkins ³, Kosala N Dissanayake ⁵, Yosua Kristaryanto ⁶, Ross A Jones ³, Julie Vogt ⁷, Manon Rivagorda ¹, Mark T Handley ¹, Girish R Mali ¹, Tooba Quidwai ¹, Dinesh C Soares ⁸, Margaret A Keighren ¹, Lisa McKie ¹, Richard L Mort ¹, Noor Gammoh ⁹, Amaya Garcia-Munoz ¹⁰, Tracey Davey ¹¹, Matthieu Vermeren ¹, Diana Walsh ⁷, Peter Budd ¹, Irene A Aligianis ¹, Eissa Faqeih ¹², Alan J Quigley ¹³, Ian J Jackson ¹, Yogesh Kulathu ⁶, Mandy Jackson ³, Richard R Ribchester ⁵, Alex von Kriegsheim ¹⁴, Fowzan S Alkuraya ¹⁵, C Geoffrey Woods ², Eamonn R Maher ¹⁶, Pleasantine Mill ¹⁷

Affiliations

1 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
2 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.
3 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.
4 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
5 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.
6 MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, UK.
7 West Midlands Regional Genetics Service, Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
8 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.
9 Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
10 Systems Biology Ireland, University College Dublin, Dublin, Ireland.
11 Electron Microscopy Research Services, Newcastle University, Newcastle NE2 4HH, UK.
12 Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh 11211, Saudi Arabia.
13 NHS Lothian, Department of Paediatric Radiology, Royal Hospital for Sick Children, Edinburgh EH9 1LF, UK.
14 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.
15 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.
16 Department of Medical Genetics, University of Cambridge, and Cambridge NIHR Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge CB2 OXY, UK. Electronic address: [email protected].
17 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address: [email protected].

PMID: 28413018 DOI: 10.1016/j.ajhg.2017.03.008

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.

Keywords

Phospholipase A2-activating protein; Ufd3; autophagy; cerebellum; endolysosomal trafficking; microcephaly; seizures; synapse; synaptic vesicle recycling; ubiquitin.

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