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 Davey; Matthieu 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

doi:10.1016/j.ajhg.2017.03.008

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. Epub 2017 Apr 13.

Authors

Emma A Hall¹, Michael S Nahorski², Lyndsay M Murray³, Ranad Shaheen⁴, Emma Perkins³, Kosala N Dissanayake⁵, Yosua Kristaryanto⁶, Ross A Jones³, Julie Vogt⁷, Manon Rivagorda¹, Mark T Handley¹, Girish R Mali¹, Tooba Quidwai¹, Dinesh C Soares⁸, Margaret A Keighren¹, Lisa McKie¹, Richard L Mort¹, Noor Gammoh⁹, Amaya Garcia-Munoz¹⁰, Tracey Davey¹¹, Matthieu Vermeren¹, Diana Walsh⁷, Peter Budd¹, Irene A Aligianis¹, Eissa Faqeih¹², Alan J Quigley¹³, Ian J Jackson¹, Yogesh Kulathu⁶, Mandy Jackson³, Richard R Ribchester⁵, Alex von Kriegsheim¹⁴, Fowzan S Alkuraya¹⁵, C Geoffrey Woods², Eamonn R Maher¹⁶, Pleasantine Mill¹⁷

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: erm1000@medschl.cam.ac.uk.
¹⁷ 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.

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.

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
Disease Models, Animal
Epilepsy / diagnosis
Epilepsy / genetics*
Fibroblasts / metabolism
Genotyping Techniques
Humans
Infant
Infant, Newborn
Magnetic Resonance Imaging
Mice
Mice, Transgenic
Mutation
Proteasome Endopeptidase Complex / genetics
Proteasome Endopeptidase Complex / metabolism
Protein Conformation
Proteins / genetics*
Proteins / metabolism
Purkinje Cells / metabolism
Spasms, Infantile / diagnosis
Spasms, Infantile / genetics*
Synaptic Transmission*
Synaptic Vesicles / metabolism
Transcriptome
Ubiquitin / genetics
Ubiquitin / metabolism

Substances

Adaptor Proteins, Signal Transducing
Proteins
Ubiquitin
phospholipase A2-activating protein
Proteasome Endopeptidase Complex

Abstract

MeSH terms

Substances

Grants and funding