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

• Published in: American journal of human genetics Vol. 100; no. 5; pp. 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: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.05.2017; Elsevier
• 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; microcephaly; Phospholipase A2-activating protein; autophagy; synaptic vesicle recycling; Ufd3; seizures; synapse; endolysosomal trafficking; ubiquitin; cerebellum
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2017.03.008

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.