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

Emma A. Hall; Michael S. Nahorski; Lyndsay M. Murray; Ranad Shaheen; Emma Perkins; Kosala N. Dissanayake; Yosua Kristaryanto; Ross A. Jones; Julie Vogt; Manon Rivagorda; Mark T. Handley; Girish R. Mali; Tooba Quidwai; Dinesh C. Soares; Margaret A. Keighren; Lisa McKie; Richard L. Mort; Noor Gammoh; Amaya Garcia-Munoz; Tracey Davey; Matthieu Vermeren; Diana Walsh; Peter Budd; Irene A. Aligianis; Eissa Faqeih; Alan J. Quigley; Ian J. Jackson; Yogesh Kulathu; Mandy Jackson; Richard R. Ribchester; Alex von Kriegsheim; Fowzan S. Alkuraya; C. Geoffrey Woods; Eamonn R. Maher; Pleasantine Mill

doi:10.1016/j.ajhg.2017.03.008

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

Emma A. Hall, Michael S. Nahorski, Lyndsay M. Murray, Ranad Shaheen, Emma Perkins, Kosala N. Dissanayake, Yosua Kristaryanto, Ross A. Jones, Julie Vogt, Manon Rivagorda, Mark T. Handley, Girish R. Mali, Tooba Quidwai, Dinesh C. Soares, Margaret A. Keighren, Lisa McKie, Richard L. Mort, Noor Gammoh, Amaya Garcia-Munoz, Tracey DaveyMatthieu Vermeren, Diana Walsh, Peter Budd, Irene A. Aligianis, Eissa Faqeih, Alan J. Quigley, Ian J. Jackson, Yogesh Kulathu, Mandy Jackson, Richard R. Ribchester, Alex von Kriegsheim, Fowzan S. Alkuraya, C. Geoffrey Woods, Eamonn R. Maher, Pleasantine Mill

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	706-724
Journal	American Journal of Human Genetics
Volume	100
Issue number	5
Early online date	13 Apr 2017
DOIs	https://doi.org/10.1016/j.ajhg.2017.03.008
Publication status	Published - 4 May 2017

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Noor Gammoh
- Deanery of Molecular, Genetic and Population Health Sciences - Reader
- Edinburgh Cancer Research Centre
Person: Academic: Research Active
Mandy Jackson
Person: Academic: Research Active
Ross Jones
- Deanery of Biomedical Sciences - Senior Lecturer
- Centre for Discovery Brain Sciences
- Euan MacDonald Centre for Motor Neuron Disease Research
- Edinburgh Neuroscience - Lecturer in Clinical/Surgical Anatomy
Person: Academic: Research Active

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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

@article{9257f8fde1bb456682155d2baf58ee3d,

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.",

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",

year = "2017",

month = may,

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doi = "10.1016/j.ajhg.2017.03.008",

language = "English",

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journal = "American Journal of Human Genetics",

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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

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

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.

U2 - 10.1016/j.ajhg.2017.03.008

DO - 10.1016/j.ajhg.2017.03.008

M3 - Article

VL - 100

SP - 706

EP - 724

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -

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

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