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

Research output: Contribution to journalJournal articlepeer-review

  • 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
  • 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
<mark>Journal publication date</mark>4/05/2017
<mark>Journal</mark>American Journal of Human Genetics
Issue number5
Number of pages19
Pages (from-to)706-724
Publication StatusPublished
Early online date13/04/17
<mark>Original language</mark>English


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.