Final published version
Licence: CC BY: Creative Commons Attribution 4.0 International License
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins
AU - Hall, Emma A.
AU - Nahorski, Michael S.
AU - Murray, Lyndsay M.
AU - Shaheen, Ranad
AU - Perkins, Emma
AU - Dissanayake, Kosala N.
AU - Kristaryanto, Yosua
AU - Jones, Ross A.
AU - Vogt, Julie
AU - Rivagorda, Manon
AU - Handley, Mark T.
AU - Mali, Girish R.
AU - Quidwai, Tooba
AU - Soares, Dinesh C.
AU - Keighren, Margaret A.
AU - McKie, Lisa
AU - Mort, Richard L.
AU - Gammoh, Noor
AU - Garcia-Munoz, Amaya
AU - Davey, Tracey
AU - Vermeren, Matthieu
AU - Walsh, Diana
AU - Budd, Peter
AU - Aligianis, Irene A.
AU - Faqeih, Eissa
AU - Quigley, Alan J.
AU - Jackson, Ian J.
AU - Kulathu, Yogesh
AU - Jackson, Mandy
AU - Ribchester, Richard R.
AU - von Kriegsheim, Alex
AU - Alkuraya, Fowzan S.
AU - Woods, C. Geoffrey
AU - Maher, Eamonn R.
AU - Mill, Pleasantine
N1 - Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2017/5/4
Y1 - 2017/5/4
N2 - 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.
AB - 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.
KW - ubiquitin
KW - endolysosomal trafficking
KW - autophagy
KW - synaptic vesicle recycling
KW - synapse
KW - microcephaly
KW - cerebellum
KW - Phospholipase A2-activating protein
KW - Ufd3
KW - seizures
U2 - 10.1016/j.ajhg.2017.03.008
DO - 10.1016/j.ajhg.2017.03.008
M3 - Journal article
C2 - 28413018
VL - 100
SP - 706
EP - 724
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -