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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.

SUBMITTER: Hall EA 

PROVIDER: S-EPMC5420347 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Hall Emma A EA   Nahorski Michael S MS   Murray Lyndsay M LM   Shaheen Ranad R   Perkins Emma E   Dissanayake Kosala N KN   Kristaryanto Yosua Y   Jones Ross A RA   Vogt Julie J   Rivagorda Manon M   Handley Mark T MT   Mali Girish R GR   Quidwai Tooba T   Soares Dinesh C DC   Keighren Margaret A MA   McKie Lisa L   Mort Richard L RL   Gammoh Noor N   Garcia-Munoz Amaya A   Davey Tracey T   Vermeren Matthieu M   Walsh Diana D   Budd Peter P   Aligianis Irene A IA   Faqeih Eissa E   Quigley Alan J AJ   Jackson Ian J IJ   Kulathu Yogesh Y   Jackson Mandy M   Ribchester Richard R RR   von Kriegsheim Alex A   Alkuraya Fowzan S FS   Woods C Geoffrey CG   Maher Eamonn R ER   Mill Pleasantine P  

American journal of human genetics 20170413 5


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  ...[more]

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