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

Research output: Contribution to Journal/Magazine › Journal article › peer-review

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PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins. / Hall, Emma A.; Nahorski, Michael S.; Murray, Lyndsay M. et al.
In: American Journal of Human Genetics, Vol. 100, No. 5, 04.05.2017, p. 706-724.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Hall, EA, Nahorski, MS, 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, Woods, CG, Maher, ER & Mill, P 2017, 'PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins', American Journal of Human Genetics, vol. 100, no. 5, pp. 706-724. https://doi.org/10.1016/j.ajhg.2017.03.008

APA

Hall, E. A., Nahorski, M. S., Murray, L. M., Shaheen, R., Perkins, E., Dissanayake, K. N., Kristaryanto, Y., Jones, R. A., Vogt, J., Rivagorda, M., Handley, M. T., Mali, G. R., Quidwai, T., Soares, D. C., Keighren, M. A., McKie, L., Mort, R. L., Gammoh, N., Garcia-Munoz, A., ... Mill, P. (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

Vancouver

Hall EA, Nahorski MS, Murray LM, Shaheen R, Perkins E, Dissanayake KN et al. PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins. American Journal of Human Genetics. 2017 May 4;100(5):706-724. Epub 2017 Apr 13. doi: 10.1016/j.ajhg.2017.03.008

Author

Hall, Emma A. ; Nahorski, Michael S. ; Murray, Lyndsay M. et al. / PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins. In: American Journal of Human Genetics. 2017 ; Vol. 100, No. 5. pp. 706-724.

Bibtex

@article{c32842a46fe44261bd8e393674a94ffd,
title = "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.",
keywords = "ubiquitin, endolysosomal trafficking, autophagy, synaptic vesicle recycling, synapse, microcephaly, cerebellum, Phospholipase A2-activating protein, Ufd3, seizures",
author = "Hall, {Emma A.} and Nahorski, {Michael S.} and Murray, {Lyndsay M.} and Ranad Shaheen and Emma Perkins and Dissanayake, {Kosala N.} and Yosua Kristaryanto and Jones, {Ross A.} and Julie Vogt and Manon Rivagorda and Handley, {Mark T.} and Mali, {Girish R.} and Tooba Quidwai and Soares, {Dinesh C.} and Keighren, {Margaret A.} and Lisa McKie and Mort, {Richard L.} and Noor Gammoh and Amaya Garcia-Munoz and Tracey Davey and Matthieu Vermeren and Diana Walsh and Peter Budd and Aligianis, {Irene A.} and Eissa Faqeih and Quigley, {Alan J.} and Jackson, {Ian J.} and Yogesh Kulathu and Mandy Jackson and Ribchester, {Richard R.} and {von Kriegsheim}, Alex and Alkuraya, {Fowzan S.} and Woods, {C. Geoffrey} and Maher, {Eamonn R.} and Pleasantine Mill",
note = "Copyright {\textcopyright} 2017 The Author(s). Published by Elsevier Inc. All rights reserved.",
year = "2017",
month = may,
day = "4",
doi = "10.1016/j.ajhg.2017.03.008",
language = "English",
volume = "100",
pages = "706--724",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "5",

}

RIS

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 -