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
Number of pages	19
Journal	American Journal of Human Genetics
Volume	100
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2017.03.008
Publication status	Published - 4 May 2017

Keywords

Adaptor Proteins, Signal Transducing/genetics
Animals
Disease Models, Animal
Epilepsy/diagnosis
Fibroblasts/metabolism
Genotyping Techniques
Humans
Infant
Infant, Newborn
Magnetic Resonance Imaging
Mice
Mice, Transgenic
Mutation
Proteasome Endopeptidase Complex/genetics
Protein Conformation
Proteins/genetics
Purkinje Cells/metabolism
Spasms, Infantile/diagnosis
Synaptic Transmission
Synaptic Vesicles/metabolism
Transcriptome
Ubiquitin/genetics

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10.1016/j.ajhg.2017.03.008Licence: CC BY 4.0

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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

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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 = "Adaptor Proteins, Signal Transducing/genetics, Animals, Disease Models, Animal, Epilepsy/diagnosis, Fibroblasts/metabolism, Genotyping Techniques, Humans, Infant, Infant, Newborn, Magnetic Resonance Imaging, Mice, Mice, Transgenic, Mutation, Proteasome Endopeptidase Complex/genetics, Protein Conformation, Proteins/genetics, Purkinje Cells/metabolism, Spasms, Infantile/diagnosis, Synaptic Transmission, Synaptic Vesicles/metabolism, Transcriptome, Ubiquitin/genetics",

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,

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",

}

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.

KW - Adaptor Proteins, Signal Transducing/genetics

KW - Animals

KW - Disease Models, Animal

KW - Epilepsy/diagnosis

KW - Fibroblasts/metabolism

KW - Genotyping Techniques

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Magnetic Resonance Imaging

KW - Mice

KW - Mice, Transgenic

KW - Mutation

KW - Proteasome Endopeptidase Complex/genetics

KW - Protein Conformation

KW - Proteins/genetics

KW - Purkinje Cells/metabolism

KW - Spasms, Infantile/diagnosis

KW - Synaptic Transmission

KW - Synaptic Vesicles/metabolism

KW - Transcriptome

KW - Ubiquitin/genetics

UR - https://www.sciencedirect.com/science/article/pii/S0002929717301131?via%3Dihub

U2 - 10.1016/j.ajhg.2017.03.008

DO - 10.1016/j.ajhg.2017.03.008

M3 - Article

C2 - 28413018

SN - 0002-9297

VL - 100

SP - 706

EP - 724

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

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

Abstract

Keywords

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