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

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-proteasom...

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Bibliographic Details
Published in:American journal of human genetics 2017-05, Vol.100 (5), p.706-724
Main Authors: Hall, Emma A., Nahorski, Michael S., Murray, Lyndsay M., Shaheen, Ranad, Perkins, Emma, Dissanayake, Kosala N., Kristaryanto, Yosua, Jones, Ross A., Vogt, Julie, Rivagorda, Manon, Handley, Mark T., Mali, Girish R., Quidwai, Tooba, Soares, Dinesh C., Keighren, Margaret A., McKie, Lisa, Mort, Richard L., Gammoh, Noor, Garcia-Munoz, Amaya, Davey, Tracey, Vermeren, Matthieu, Walsh, Diana, Budd, Peter, Aligianis, Irene A., Faqeih, Eissa, Quigley, Alan J., Jackson, Ian J., Kulathu, Yogesh, Jackson, Mandy, Ribchester, Richard R., von Kriegsheim, Alex, Alkuraya, Fowzan S., Woods, C. Geoffrey, Maher, Eamonn R., Mill, Pleasantine
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Animals
autophagy
cerebellum
Disease Models, Animal
endolysosomal trafficking
Epilepsy - diagnosis
Epilepsy - genetics
Fibroblasts - metabolism
Genotyping Techniques
Humans
Infant
Infant, Newborn
Magnetic Resonance Imaging
Mice
Mice, Transgenic
microcephaly
Mutation
Phospholipase A2-activating protein
Proteasome Endopeptidase Complex - genetics
Proteasome Endopeptidase Complex - metabolism
Protein Conformation
Proteins - genetics
Proteins - metabolism
Purkinje Cells - metabolism
seizures
Spasms, Infantile - diagnosis
Spasms, Infantile - genetics
synapse
Synaptic Transmission
synaptic vesicle recycling
Synaptic Vesicles - metabolism
Transcriptome
ubiquitin
Ubiquitin - genetics
Ubiquitin - metabolism
Ufd3
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Description
Summary: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.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2017.03.008