PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins.
Authors
Hall, EA
Nahorski, Michael Stefan
Murray, LM
Shaheen, R
Perkins, E
Dissanayake, KN
Kristaryanto, Y
Jones, RA
Vogt, J
Rivagorda, M
Handley, MT
Mali, GR
Quidwai, T
Soares, DC
Keighren, MA
McKie, L
Mort, RL
Gammoh, N
Garcia-Munoz, A
Davey, T
Vermeren, M
Walsh, D
Budd, P
Aligianis, IA
Faqeih, E
Quigley, AJ
Jackson, IJ
Kulathu, Y
Jackson, M
Ribchester, RR
von Kriegsheim, A
Alkuraya, FS
Mill, P
Publication Date
2017-05-04Journal Title
American Journal of Human Genetics
ISSN
0002-9297
Publisher
Elsevier
Volume
100
Issue
5
Pages
706-724
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Hall, E., Nahorski, M. S., Murray, L., Shaheen, R., Perkins, E., Dissanayake, K., Kristaryanto, Y., et al. (2017). PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins.. American Journal of Human Genetics, 100 (5), 706-724. https://doi.org/10.1016/j.ajhg.2017.03.008
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
Sponsorship
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.).
Funder references
Cambridge University Hospitals NHS Foundation Trust (CUH) (1831 R7002)
Addenbrooke's Charitable Trust (ACT) (9158)
Wellcome Trust (via University College London (UCL)) (532344)
Identifiers
External DOI: https://doi.org/10.1016/j.ajhg.2017.03.008
This record's URL: https://www.repository.cam.ac.uk/handle/1810/264425
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International