Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS

Claire E Hall; Zhi Yao; Minee Choi; Giulia E Tyzack; Andrea Serio; Raphaelle  Luisier; Jasmine  Harely; Elisavet Preza; Charlie  Arber; Sarah J Crisp; P Marc D Watson; Dimitri  Kullmann; Andrey Abramov; Selina Wray; Russell Burley; Samantha HY Loh; Miguel Martins; Molly Stevens; Nicholas M. Luscombe; Christopher R Sibley; Andras Lakatos; Jernej Ule; Sonia Gandhi; Rickie Patani

doi:10.1016/j.celrep.2017.05.024

Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS

Claire E Hall, Zhi Yao, Minee Choi, Giulia E Tyzack, Andrea Serio, Raphaelle Luisier, Jasmine Harely, Elisavet Preza, Charlie Arber, Sarah J Crisp, P Marc D Watson, Dimitri Kullmann, Andrey Abramov, Selina Wray, Russell Burley, Samantha HY Loh, Miguel Martins, Molly Stevens, Nicholas M. Luscombe, Christopher R SibleyAndras Lakatos, Jernej Ule, Sonia Gandhi, Rickie Patani

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Abstract

Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell-autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay that could guide future therapeutic strategies in ALS.

Original language	English
Pages (from-to)	1739-1749
Journal	Cell Reports
Volume	19
Issue number	9
Early online date	30 May 2017
DOIs	https://doi.org/10.1016/j.celrep.2017.05.024
Publication status	Published - 30 May 2017

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Progressive Motor Neuron Pathology_HALL_Publishedonline30May2017_GOLD VoR (CC BY)Final published version, 3.49 MBLicence: CC BY

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Hall, C. E., Yao, Z., Choi, M., Tyzack, G. E., Serio, A., Luisier, R., Harely, J., Preza, E., Arber, C., Crisp, S. J., Watson, P. M. D., Kullmann, D., Abramov, A., Wray, S., Burley, R., Loh, S. HY., Martins, M., Stevens, M., Luscombe, N. M., ... Patani, R. (2017). Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS. Cell Reports, 19(9), 1739-1749. https://doi.org/10.1016/j.celrep.2017.05.024

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title = "Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS",

abstract = "Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell-autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay that could guide future therapeutic strategies in ALS.",

author = "Hall, {Claire E} and Zhi Yao and Minee Choi and Tyzack, {Giulia E} and Andrea Serio and Raphaelle Luisier and Jasmine Harely and Elisavet Preza and Charlie Arber and Crisp, {Sarah J} and Watson, {P Marc D} and Dimitri Kullmann and Andrey Abramov and Selina Wray and Russell Burley and Loh, {Samantha HY} and Miguel Martins and Molly Stevens and Luscombe, {Nicholas M.} and Sibley, {Christopher R} and Andras Lakatos and Jernej Ule and Sonia Gandhi and Rickie Patani",

year = "2017",

month = may,

day = "30",

doi = "10.1016/j.celrep.2017.05.024",

language = "English",

volume = "19",

pages = "1739--1749",

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Hall, CE, Yao, Z, Choi, M, Tyzack, GE, Serio, A, Luisier, R, Harely, J, Preza, E, Arber, C, Crisp, SJ, Watson, PMD, Kullmann, D, Abramov, A, Wray, S, Burley, R, Loh, SHY, Martins, M, Stevens, M, Luscombe, NM, Sibley, CR, Lakatos, A, Ule, J, Gandhi, S & Patani, R 2017, 'Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS', Cell Reports, vol. 19, no. 9, pp. 1739-1749. https://doi.org/10.1016/j.celrep.2017.05.024

TY - JOUR

T1 - Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS

AU - Hall, Claire E

AU - Yao, Zhi

AU - Choi, Minee

AU - Tyzack, Giulia E

AU - Serio, Andrea

AU - Luisier, Raphaelle

AU - Harely, Jasmine

AU - Preza, Elisavet

AU - Arber, Charlie

AU - Crisp, Sarah J

AU - Watson, P Marc D

AU - Kullmann, Dimitri

AU - Abramov, Andrey

AU - Wray, Selina

AU - Burley, Russell

AU - Loh, Samantha HY

AU - Martins, Miguel

AU - Stevens, Molly

AU - Luscombe, Nicholas M.

AU - Sibley, Christopher R

AU - Lakatos, Andras

AU - Ule, Jernej

AU - Gandhi, Sonia

AU - Patani, Rickie

PY - 2017/5/30

Y1 - 2017/5/30

N2 - Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell-autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay that could guide future therapeutic strategies in ALS.

AB - Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell-autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay that could guide future therapeutic strategies in ALS.

U2 - 10.1016/j.celrep.2017.05.024

DO - 10.1016/j.celrep.2017.05.024

M3 - Article

SN - 2211-1247

VL - 19

SP - 1739

EP - 1749

JO - Cell Reports

JF - Cell Reports

IS - 9

ER -

Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS

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