ArticleAmerican journal of human genetics2017
PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins.
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Article in American journal of human genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 48 citations in OpenAlex.
- Ubiquitination in the Nervous System: From Molecular Mechanisms to Disease Implications.Molecular neurobiology · 2025Review
- PLAA/UFD-3 regulates P-bodies through its intrinsic disordered domain.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Axonal transport of CHMP2b is regulated by kinesin-binding protein and disrupted by CHMP2bLife science alliance · 2025Article
- Genetic Alterations in Atypical Cerebral Palsy Identified Through Chromosomal Microarray and Exome Sequencing.International journal of molecular sciences · 2025Article
- Allelic heterogeneity and abnormal vesicle recycling inFrontiers in molecular neuroscience · 2024Article
- p97/VCP Promotes the Recycling of Endocytic Cargo.Molecular biology of the cell · 2023Article
- Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases.Molecular neurodegeneration · 2023Review
- The UBX domain in UBXD1 organizes ubiquitin binding at the C-terminus of the VCP/p97 AAA-ATPase.Nature communications · 2023Article
- Targeting of client proteins to the VCP/p97/Cdc48 unfolding machine.Frontiers in molecular biosciences · 2023Review
- NMJ-related diseases beyond the congenital myasthenic syndromes.Frontiers in cell and developmental biology · 2023Review
- Axonal transport of Hrs is activity dependent and facilitates synaptic vesicle protein degradation.Life science alliance · 2022Article
- The Cure VCP Scientific Conference 2021: Molecular and clinical insights into neurodegeneration and myopathy linked to multisystem proteinopathy-1 (MSP-1).Neurobiology of disease · 2022Review
- Membrane lipid raft homeostasis is directly linked to neurodegeneration.Essays in biochemistry · 2021Review
- Neuronal VCP loss of function recapitulates FTLD-TDP pathology.Cell reports · 2021Article
- The Ubiquitinated Axon: Local Control of Axon Development and Function by Ubiquitin.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Review
- Microsomic and macrosomic body structure in children and adolescents affected by syndromes or diseases associated with neurodysfunction.Scientific reports · 2021Article
- Remodeling without destruction: non-proteolytic ubiquitin chains in neural function and brain disorders.Molecular psychiatry · 2021Review
- Cholesterol transport between red blood cells and lipoproteins contributes to cholesterol metabolism in blood.Journal of lipid research · 2020Article
- Microinjection induces changes in the transcriptome of bovine oocytes.Scientific reports · 2020Article
- mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update.International journal of molecular sciences · 2020Review
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Authors and funding
35 authors at 12 institutions in 3 countries.
Emma A HallMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Michael S NahorskiCambridge 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.
Lyndsay M MurrayCentre 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.
Ranad ShaheenDepartment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Emma PerkinsCentre 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.
Kosala N DissanayakeEuan 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.
Yosua KristaryantoMRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, UK.
Ross A JonesCentre 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.
Julie VogtWest Midlands Regional Genetics Service, Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
Manon RivagordaMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Mark T HandleyMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Girish R MaliMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Tooba QuidwaiMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Dinesh C SoaresMRC 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.
Margaret A KeighrenMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Lisa McKieMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Richard L MortMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Noor GammohEdinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Amaya Garcia-MunozSystems Biology Ireland, University College Dublin, Dublin, Ireland.
Tracey DaveyElectron Microscopy Research Services, Newcastle University, Newcastle NE2 4HH, UK.
Matthieu VermerenMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Diana WalshWest Midlands Regional Genetics Service, Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
Peter BuddMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Irene A AligianisMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Eissa FaqeihDepartment of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh 11211, Saudi Arabia.
Alan J QuigleyNHS Lothian, Department of Paediatric Radiology, Royal Hospital for Sick Children, Edinburgh EH9 1LF, UK.
Ian J JacksonMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Yogesh KulathuMRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, UK.
Mandy JacksonCentre 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.
Richard R RibchesterEuan 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.
Alex von KriegsheimEdinburgh 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.
Fowzan S AlkurayaDepartment 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.
C Geoffrey WoodsCambridge 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.
Eamonn R MaherDepartment 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.
Pleasantine MillMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address: pleasantine.mill@igmm.ed.ac.uk.
University of Edinburgh · GBMRC Institute of Genetics and Molecular Medicine · GBUniversity of Cambridge · GBBirmingham Women's Hospital · GBEdinburgh Cancer Research · GBKing Faisal Specialist Hospital & Research Centre · SAKing Fahd Medical City · SAMRC Protein Phosphorylation and Ubiquitylation Unit · GBNewcastle University · GBRoyal Hospital for Sick Children · GBUniversity College Dublin · IEUniversity of Dundee · GB
Funding
Medical Research Council MC_PC_U127527200Medical Research Council MC_PC_U127561112Medical Research Council MC_UU_12016/6Medical Research Council MC_UU_12018/26Medical Research Council MR/M024075/1Wellcome Trust
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.
Indexed as
Synaptic TransmissionAdaptor Proteins, Signal TransducingAnimalsDisease Models, AnimalEpilepsyFibroblastsGenotyping TechniquesHumansInfantInfant, NewbornMagnetic Resonance ImagingMiceMice, TransgenicMutationProteasome Endopeptidase ComplexProtein ConformationAdaptor Proteins, Signal Transducingphospholipase A2-activating proteinProteasome Endopeptidase ComplexProteinsUbiquitinautophagycerebellumendolysosomal traffickingmicrocephalyPhospholipase A2-activating proteinseizuressynapsesynaptic vesicle recyclingubiquitinUfd3
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