Mutations in FUS lead to synaptic dysregulation in ALS-iPSC derived neurons

Carole Shum; Erin C. Hedges; Joseph Allison; Youn bok Lee; Natalia Arias; Graham Cocks; Siddharthan Chandran; Marc David Ruepp; Christopher E. Shaw; Agnes L. Nishimura

doi:10.1016/j.stemcr.2023.12.007

Mutations in FUS lead to synaptic dysregulation in ALS-iPSC derived neurons

Carole Shum, Erin C. Hedges, Joseph Allison, Youn bok Lee, Natalia Arias, Graham Cocks, Siddharthan Chandran, Marc David Ruepp, Christopher E. Shaw^*, Agnes L. Nishimura^*

^*Corresponding author for this work

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

2 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disorder characterized by progressive muscular weakness due to the selective loss of motor neurons. Mutations in the gene Fused in Sarcoma (FUS) were identified as one cause of ALS. Here, we report that mutations in FUS lead to upregulation of synaptic proteins, increasing synaptic activity and abnormal release of vesicles at the synaptic cleft. Consequently, FUS-ALS neurons showed greater vulnerability to glutamate excitotoxicity, which raised neuronal swellings (varicose neurites) and led to neuronal death. Fragile X mental retardation protein (FMRP) is an RNA-binding protein known to regulate synaptic protein translation, and its expression is reduced in the FUS-ALS lines. Collectively, our data suggest that a reduction of FMRP levels alters the synaptic protein dynamics, leading to synaptic dysfunction and glutamate excitotoxicity. Here, we present a mechanistic hypothesis linking dysregulation of peripheral translation with synaptic vulnerability in the pathogenesis of FUS-ALS.

Original language	English
Pages (from-to)	187-195
Number of pages	9
Journal	Stem cell reports
Volume	19
Issue number	2
DOIs	https://doi.org/10.1016/j.stemcr.2023.12.007
Publication status	Published - 18 Jan 2024

Keywords

ALS
amyotrophic lateral sclerosis
disease modelling
FMRP
fragile X mental retardation protein
FUS
fused in sarcoma
induced pluripotent stem cells
iPSCs
neuronal degeneration
synaptic dysfunction

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.stemcr.2023.12.007

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@article{085d479ffa244b6c8ffe1cb14770b7cd,

title = "Mutations in FUS lead to synaptic dysregulation in ALS-iPSC derived neurons",

abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disorder characterized by progressive muscular weakness due to the selective loss of motor neurons. Mutations in the gene Fused in Sarcoma (FUS) were identified as one cause of ALS. Here, we report that mutations in FUS lead to upregulation of synaptic proteins, increasing synaptic activity and abnormal release of vesicles at the synaptic cleft. Consequently, FUS-ALS neurons showed greater vulnerability to glutamate excitotoxicity, which raised neuronal swellings (varicose neurites) and led to neuronal death. Fragile X mental retardation protein (FMRP) is an RNA-binding protein known to regulate synaptic protein translation, and its expression is reduced in the FUS-ALS lines. Collectively, our data suggest that a reduction of FMRP levels alters the synaptic protein dynamics, leading to synaptic dysfunction and glutamate excitotoxicity. Here, we present a mechanistic hypothesis linking dysregulation of peripheral translation with synaptic vulnerability in the pathogenesis of FUS-ALS.",

keywords = "ALS, amyotrophic lateral sclerosis, disease modelling, FMRP, fragile X mental retardation protein, FUS, fused in sarcoma, induced pluripotent stem cells, iPSCs, neuronal degeneration, synaptic dysfunction",

author = "Carole Shum and Hedges, {Erin C.} and Joseph Allison and Lee, {Youn bok} and Natalia Arias and Graham Cocks and Siddharthan Chandran and Ruepp, {Marc David} and Shaw, {Christopher E.} and Nishimura, {Agnes L.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2024",

month = jan,

day = "18",

doi = "10.1016/j.stemcr.2023.12.007",

language = "English",

volume = "19",

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journal = "Stem cell reports",

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TY - JOUR

T1 - Mutations in FUS lead to synaptic dysregulation in ALS-iPSC derived neurons

AU - Shum, Carole

AU - Hedges, Erin C.

AU - Allison, Joseph

AU - Lee, Youn bok

AU - Arias, Natalia

AU - Cocks, Graham

AU - Chandran, Siddharthan

AU - Ruepp, Marc David

AU - Shaw, Christopher E.

AU - Nishimura, Agnes L.

PY - 2024/1/18

Y1 - 2024/1/18

N2 - Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disorder characterized by progressive muscular weakness due to the selective loss of motor neurons. Mutations in the gene Fused in Sarcoma (FUS) were identified as one cause of ALS. Here, we report that mutations in FUS lead to upregulation of synaptic proteins, increasing synaptic activity and abnormal release of vesicles at the synaptic cleft. Consequently, FUS-ALS neurons showed greater vulnerability to glutamate excitotoxicity, which raised neuronal swellings (varicose neurites) and led to neuronal death. Fragile X mental retardation protein (FMRP) is an RNA-binding protein known to regulate synaptic protein translation, and its expression is reduced in the FUS-ALS lines. Collectively, our data suggest that a reduction of FMRP levels alters the synaptic protein dynamics, leading to synaptic dysfunction and glutamate excitotoxicity. Here, we present a mechanistic hypothesis linking dysregulation of peripheral translation with synaptic vulnerability in the pathogenesis of FUS-ALS.

AB - Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disorder characterized by progressive muscular weakness due to the selective loss of motor neurons. Mutations in the gene Fused in Sarcoma (FUS) were identified as one cause of ALS. Here, we report that mutations in FUS lead to upregulation of synaptic proteins, increasing synaptic activity and abnormal release of vesicles at the synaptic cleft. Consequently, FUS-ALS neurons showed greater vulnerability to glutamate excitotoxicity, which raised neuronal swellings (varicose neurites) and led to neuronal death. Fragile X mental retardation protein (FMRP) is an RNA-binding protein known to regulate synaptic protein translation, and its expression is reduced in the FUS-ALS lines. Collectively, our data suggest that a reduction of FMRP levels alters the synaptic protein dynamics, leading to synaptic dysfunction and glutamate excitotoxicity. Here, we present a mechanistic hypothesis linking dysregulation of peripheral translation with synaptic vulnerability in the pathogenesis of FUS-ALS.

KW - ALS

KW - amyotrophic lateral sclerosis

KW - disease modelling

KW - FMRP

KW - fragile X mental retardation protein

KW - FUS

KW - fused in sarcoma

KW - induced pluripotent stem cells

KW - iPSCs

KW - neuronal degeneration

KW - synaptic dysfunction

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U2 - 10.1016/j.stemcr.2023.12.007

DO - 10.1016/j.stemcr.2023.12.007

M3 - Article

C2 - 38242131

AN - SCOPUS:85184885726

SN - 2213-6711

VL - 19

SP - 187

EP - 195

JO - Stem cell reports

JF - Stem cell reports

IS - 2

ER -

Mutations in FUS lead to synaptic dysregulation in ALS-iPSC derived neurons

Abstract

Keywords

UN SDGs

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