Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability

Anna-Claire Devlin; Karen Burr; Shyamanga Borooah; Joshua D Foster; Elaine M Cleary; Imbisaat Geti; Ludovic Vallier; Christopher E Shaw; Siddharthan Chandran; Gareth B Miles

doi:10.1038/ncomms6999

Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability

Anna-Claire Devlin, Karen Burr, Shyamanga Borooah, Joshua D Foster, Elaine M Cleary, Imbisaat Geti, Ludovic Vallier, Christopher E Shaw, Siddharthan Chandran, Gareth B Miles

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Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which a greater understanding of early disease mechanisms is needed to reveal novel therapeutic targets. We report the use of human induced pluripotent stem cell (iPSC)-derived motoneurons (MNs) to study the pathophysiology of ALS. We demonstrate that MNs derived from iPSCs obtained from healthy individuals or patients harbouring TARDBP or C9ORF72 ALS-causing mutations are able to develop appropriate physiological properties. However, patient iPSC-derived MNs, independent of genotype, display an initial hyperexcitability followed by progressive loss of action potential output and synaptic activity. This loss of functional output reflects a progressive decrease in voltage-activated Na⁺ and K⁺ currents, which occurs in the absence of overt changes in cell viability. These data implicate early dysfunction or loss of ion channels as a convergent point that may contribute to the initiation of downstream degenerative pathways that ultimately lead to MN loss in ALS.

Original language	English
Article number	5999
Number of pages	12
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms6999
Publication status	Published - 12 Jan 2015

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Cite this

@article{bb4d1a4d01384465aed95a80eade4dc0,

title = "Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability",

abstract = "Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which a greater understanding of early disease mechanisms is needed to reveal novel therapeutic targets. We report the use of human induced pluripotent stem cell (iPSC)-derived motoneurons (MNs) to study the pathophysiology of ALS. We demonstrate that MNs derived from iPSCs obtained from healthy individuals or patients harbouring TARDBP or C9ORF72 ALS-causing mutations are able to develop appropriate physiological properties. However, patient iPSC-derived MNs, independent of genotype, display an initial hyperexcitability followed by progressive loss of action potential output and synaptic activity. This loss of functional output reflects a progressive decrease in voltage-activated Na+ and K+ currents, which occurs in the absence of overt changes in cell viability. These data implicate early dysfunction or loss of ion channels as a convergent point that may contribute to the initiation of downstream degenerative pathways that ultimately lead to MN loss in ALS.",

author = "Anna-Claire Devlin and Karen Burr and Shyamanga Borooah and Foster, {Joshua D} and Cleary, {Elaine M} and Imbisaat Geti and Ludovic Vallier and Shaw, {Christopher E} and Siddharthan Chandran and Miles, {Gareth B}",

note = "This work has been supported by: Motor Neurone Disease Association (G.B.M., S.C. and C.E.S.); Euan MacDonald Centre (G.B.M. and S.C.); European Research Council (L.V.); Cambridge Hospitals National Institute for Health Research Biomedical Research Center (L.V.).",

year = "2015",

month = jan,

day = "12",

doi = "10.1038/ncomms6999",

language = "English",

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journal = "Nature Communications",

issn = "2041-1723",

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TY - JOUR

T1 - Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability

AU - Devlin, Anna-Claire

AU - Burr, Karen

AU - Borooah, Shyamanga

AU - Foster, Joshua D

AU - Cleary, Elaine M

AU - Geti, Imbisaat

AU - Vallier, Ludovic

AU - Shaw, Christopher E

AU - Chandran, Siddharthan

AU - Miles, Gareth B

N1 - This work has been supported by: Motor Neurone Disease Association (G.B.M., S.C. and C.E.S.); Euan MacDonald Centre (G.B.M. and S.C.); European Research Council (L.V.); Cambridge Hospitals National Institute for Health Research Biomedical Research Center (L.V.).

PY - 2015/1/12

Y1 - 2015/1/12

N2 - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which a greater understanding of early disease mechanisms is needed to reveal novel therapeutic targets. We report the use of human induced pluripotent stem cell (iPSC)-derived motoneurons (MNs) to study the pathophysiology of ALS. We demonstrate that MNs derived from iPSCs obtained from healthy individuals or patients harbouring TARDBP or C9ORF72 ALS-causing mutations are able to develop appropriate physiological properties. However, patient iPSC-derived MNs, independent of genotype, display an initial hyperexcitability followed by progressive loss of action potential output and synaptic activity. This loss of functional output reflects a progressive decrease in voltage-activated Na+ and K+ currents, which occurs in the absence of overt changes in cell viability. These data implicate early dysfunction or loss of ion channels as a convergent point that may contribute to the initiation of downstream degenerative pathways that ultimately lead to MN loss in ALS.

AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which a greater understanding of early disease mechanisms is needed to reveal novel therapeutic targets. We report the use of human induced pluripotent stem cell (iPSC)-derived motoneurons (MNs) to study the pathophysiology of ALS. We demonstrate that MNs derived from iPSCs obtained from healthy individuals or patients harbouring TARDBP or C9ORF72 ALS-causing mutations are able to develop appropriate physiological properties. However, patient iPSC-derived MNs, independent of genotype, display an initial hyperexcitability followed by progressive loss of action potential output and synaptic activity. This loss of functional output reflects a progressive decrease in voltage-activated Na+ and K+ currents, which occurs in the absence of overt changes in cell viability. These data implicate early dysfunction or loss of ion channels as a convergent point that may contribute to the initiation of downstream degenerative pathways that ultimately lead to MN loss in ALS.

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DO - 10.1038/ncomms6999

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SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 5999

ER -

Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability

Abstract

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Edin Uni: EMC MNDA Studentship 2014

Deciphering non-cell autonomous: Deciphering non-cell autonomous disease mechanisms in human ALS using inducible pluripotent stem (iPS) cell technology

Gareth Brian Miles

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Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability

Abstract

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Edin Uni: EMC MNDA Studentship 2014

Deciphering non-cell autonomous: Deciphering non-cell autonomous disease mechanisms in human ALS using inducible pluripotent stem (iPS) cell technology

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Gareth Brian Miles

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