@article{0c20624f6912416c8a636c7595345c55,
title = "PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins",
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 = "Journal article, Ubiquitin, Endolysosomal trafficking, Autophage, Synaptic vesicle recycling, Synapse, Microcephaly, Cerebellum, Phospholipase A2-activating protein",
author = "Hall, {Emma A.} and Nahorski, {Michael S.} and Murray, {Lyndsay M.} and Ranad Shaheen and Emma Perkins and Dissanayake, {Kosala N.} and Yosua Kristaryanto and Jones, {Ross A.} and Julie Vogt and Manon Rivagorda and Handley, {Mark T.} and Mali, {Girish R.} and Tooba Quidwai and Soares, {Dinesh C.} and Keighren, {Margaret A.} and Lisa McKie and Mort, {Richard L.} and Noor Gammoh and Amaya Garcia-Munoz and Tracey Davey and Matthieu Vermeren and Diana Walsh and Peter Budd and Aligianis, {Irene A.} and Eissa Faqeih and Quigley, {Alan J.} and Jackson, {Ian J.} and Yogesh Kulathu and Mandy Jackson and Ribchester, {Richard R.} and {von Kriegsheim}, Alex and Alkuraya, {Fowzan S.} and Woods, {C. Geoffrey} and Maher, {Eamonn R.} and Pleasantine Mill",
note = "This work was supported by core funding from the MRC (MC_UU_12018/26 to E.A.H., G.R.M., and P.M.; MC_PC_U127527200 to P.B., M.A.K., L.M., R.L.M., and I.J.J.; and MC_UU_12016/6 to Y. Kulathu and Y. Kristaryanto), MRCMICA grant (to M.S.N.), Muscular Dystrophy Association (MDA294433) (to L.M.M.), Science Foundation Ireland (13/SIRG/2174) (to A.G.-M. and A.v.K.), NIHR Cambridge BRC 2012 (to C.G.W.), MRC, Wellcome, and WellChild (to E.R.M.), and King Salman Center for Disability Research (to F.S.A.).",
year = "2017",
month = may,
day = "4",
doi = "10.1016/j.ajhg.2017.03.008",
language = "English",
volume = "100",
pages = "706--724",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "5",
}