Intrinsic Membrane Hyperexcitability of ALS Patient-Derived Motor Neurons
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multi-electrode array and patch clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cel...
Gespeichert in:
| Veröffentlicht in: | Cell reports (Cambridge) 2014-04, Vol.7 (1), p.1-11 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 11 |
|---|---|
| container_issue | 1 |
| container_start_page | 1 |
| container_title | Cell reports (Cambridge) |
| container_volume | 7 |
| creator | Wainger, Brian J. Kiskinis, Evangelos Mellin, Cassidy Wiskow, Ole Han, Steve S.W. Sandoe, Jackson Perez, Numa P. Williams, Luis A. Lee, Seungkyu Boulting, Gabriella Berry, James D. Brown, Robert H. Cudkowicz, Merit E. Bean, Bruce P. Eggan, Kevin Woolf, Clifford J. |
| description | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multi-electrode array and patch clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (
SOD1
),
C9orf72
and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected, but otherwise isogenic,
SOD1
+/+
stem cell line do not display the hyperexcitability phenotype.
SOD1
A4V/+
ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival
in vitro
when tested in
SOD1
mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates. |
| doi_str_mv | 10.1016/j.celrep.2014.03.019 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmedcentral</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4023477</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>pubmedcentral_primary_oai_pubmedcentral_nih_gov_4023477</sourcerecordid><originalsourceid>FETCH-pubmedcentral_primary_oai_pubmedcentral_nih_gov_40234773</originalsourceid><addsrcrecordid>eNqljM1KAzEUhYMgtti-gYu8wIy5Seg4G0H8oQUrQt2HzPRWb5lJhpu0OG_vLNy49mwOfIfvCHEDqgQFq9tj2WLHOJRagS2VKRXUF2KuNUAB2lYzsUzpqKasFEBtr8RsosrcmXouNpuQmUKiVm6xb9gHlOtxQMbvlrJvqKM8yniQD687-e4zYcjFEzKdcS-3MUeWb3jiGNJCXB58l3D529fi_uX543FdDKemx307iew7NzD1nkcXPbm_S6Av9xnPziptbFWZfx_8APXfXEI</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Intrinsic Membrane Hyperexcitability of ALS Patient-Derived Motor Neurons</title><source>DOAJ Directory of Open Access Journals</source><source>Cell Press Free Archives</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Wainger, Brian J. ; Kiskinis, Evangelos ; Mellin, Cassidy ; Wiskow, Ole ; Han, Steve S.W. ; Sandoe, Jackson ; Perez, Numa P. ; Williams, Luis A. ; Lee, Seungkyu ; Boulting, Gabriella ; Berry, James D. ; Brown, Robert H. ; Cudkowicz, Merit E. ; Bean, Bruce P. ; Eggan, Kevin ; Woolf, Clifford J.</creator><creatorcontrib>Wainger, Brian J. ; Kiskinis, Evangelos ; Mellin, Cassidy ; Wiskow, Ole ; Han, Steve S.W. ; Sandoe, Jackson ; Perez, Numa P. ; Williams, Luis A. ; Lee, Seungkyu ; Boulting, Gabriella ; Berry, James D. ; Brown, Robert H. ; Cudkowicz, Merit E. ; Bean, Bruce P. ; Eggan, Kevin ; Woolf, Clifford J.</creatorcontrib><description>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multi-electrode array and patch clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (
SOD1
),
C9orf72
and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected, but otherwise isogenic,
SOD1
+/+
stem cell line do not display the hyperexcitability phenotype.
SOD1
A4V/+
ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival
in vitro
when tested in
SOD1
mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.</description><identifier>EISSN: 2211-1247</identifier><identifier>DOI: 10.1016/j.celrep.2014.03.019</identifier><identifier>PMID: 24703839</identifier><language>eng</language><ispartof>Cell reports (Cambridge), 2014-04, Vol.7 (1), p.1-11</ispartof><rights>2014 Published by Elsevier Inc. All rights reserved. 2014</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,864,885,27924,27925</link.rule.ids></links><search><creatorcontrib>Wainger, Brian J.</creatorcontrib><creatorcontrib>Kiskinis, Evangelos</creatorcontrib><creatorcontrib>Mellin, Cassidy</creatorcontrib><creatorcontrib>Wiskow, Ole</creatorcontrib><creatorcontrib>Han, Steve S.W.</creatorcontrib><creatorcontrib>Sandoe, Jackson</creatorcontrib><creatorcontrib>Perez, Numa P.</creatorcontrib><creatorcontrib>Williams, Luis A.</creatorcontrib><creatorcontrib>Lee, Seungkyu</creatorcontrib><creatorcontrib>Boulting, Gabriella</creatorcontrib><creatorcontrib>Berry, James D.</creatorcontrib><creatorcontrib>Brown, Robert H.</creatorcontrib><creatorcontrib>Cudkowicz, Merit E.</creatorcontrib><creatorcontrib>Bean, Bruce P.</creatorcontrib><creatorcontrib>Eggan, Kevin</creatorcontrib><creatorcontrib>Woolf, Clifford J.</creatorcontrib><title>Intrinsic Membrane Hyperexcitability of ALS Patient-Derived Motor Neurons</title><title>Cell reports (Cambridge)</title><description>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multi-electrode array and patch clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (
SOD1
),
C9orf72
and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected, but otherwise isogenic,
SOD1
+/+
stem cell line do not display the hyperexcitability phenotype.
SOD1
A4V/+
ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival
in vitro
when tested in
SOD1
mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.</description><issn>2211-1247</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNqljM1KAzEUhYMgtti-gYu8wIy5Seg4G0H8oQUrQt2HzPRWb5lJhpu0OG_vLNy49mwOfIfvCHEDqgQFq9tj2WLHOJRagS2VKRXUF2KuNUAB2lYzsUzpqKasFEBtr8RsosrcmXouNpuQmUKiVm6xb9gHlOtxQMbvlrJvqKM8yniQD687-e4zYcjFEzKdcS-3MUeWb3jiGNJCXB58l3D529fi_uX543FdDKemx307iew7NzD1nkcXPbm_S6Av9xnPziptbFWZfx_8APXfXEI</recordid><startdate>20140403</startdate><enddate>20140403</enddate><creator>Wainger, Brian J.</creator><creator>Kiskinis, Evangelos</creator><creator>Mellin, Cassidy</creator><creator>Wiskow, Ole</creator><creator>Han, Steve S.W.</creator><creator>Sandoe, Jackson</creator><creator>Perez, Numa P.</creator><creator>Williams, Luis A.</creator><creator>Lee, Seungkyu</creator><creator>Boulting, Gabriella</creator><creator>Berry, James D.</creator><creator>Brown, Robert H.</creator><creator>Cudkowicz, Merit E.</creator><creator>Bean, Bruce P.</creator><creator>Eggan, Kevin</creator><creator>Woolf, Clifford J.</creator><scope>5PM</scope></search><sort><creationdate>20140403</creationdate><title>Intrinsic Membrane Hyperexcitability of ALS Patient-Derived Motor Neurons</title><author>Wainger, Brian J. ; Kiskinis, Evangelos ; Mellin, Cassidy ; Wiskow, Ole ; Han, Steve S.W. ; Sandoe, Jackson ; Perez, Numa P. ; Williams, Luis A. ; Lee, Seungkyu ; Boulting, Gabriella ; Berry, James D. ; Brown, Robert H. ; Cudkowicz, Merit E. ; Bean, Bruce P. ; Eggan, Kevin ; Woolf, Clifford J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmedcentral_primary_oai_pubmedcentral_nih_gov_40234773</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wainger, Brian J.</creatorcontrib><creatorcontrib>Kiskinis, Evangelos</creatorcontrib><creatorcontrib>Mellin, Cassidy</creatorcontrib><creatorcontrib>Wiskow, Ole</creatorcontrib><creatorcontrib>Han, Steve S.W.</creatorcontrib><creatorcontrib>Sandoe, Jackson</creatorcontrib><creatorcontrib>Perez, Numa P.</creatorcontrib><creatorcontrib>Williams, Luis A.</creatorcontrib><creatorcontrib>Lee, Seungkyu</creatorcontrib><creatorcontrib>Boulting, Gabriella</creatorcontrib><creatorcontrib>Berry, James D.</creatorcontrib><creatorcontrib>Brown, Robert H.</creatorcontrib><creatorcontrib>Cudkowicz, Merit E.</creatorcontrib><creatorcontrib>Bean, Bruce P.</creatorcontrib><creatorcontrib>Eggan, Kevin</creatorcontrib><creatorcontrib>Woolf, Clifford J.</creatorcontrib><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell reports (Cambridge)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wainger, Brian J.</au><au>Kiskinis, Evangelos</au><au>Mellin, Cassidy</au><au>Wiskow, Ole</au><au>Han, Steve S.W.</au><au>Sandoe, Jackson</au><au>Perez, Numa P.</au><au>Williams, Luis A.</au><au>Lee, Seungkyu</au><au>Boulting, Gabriella</au><au>Berry, James D.</au><au>Brown, Robert H.</au><au>Cudkowicz, Merit E.</au><au>Bean, Bruce P.</au><au>Eggan, Kevin</au><au>Woolf, Clifford J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intrinsic Membrane Hyperexcitability of ALS Patient-Derived Motor Neurons</atitle><jtitle>Cell reports (Cambridge)</jtitle><date>2014-04-03</date><risdate>2014</risdate><volume>7</volume><issue>1</issue><spage>1</spage><epage>11</epage><pages>1-11</pages><eissn>2211-1247</eissn><abstract>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multi-electrode array and patch clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (
SOD1
),
C9orf72
and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected, but otherwise isogenic,
SOD1
+/+
stem cell line do not display the hyperexcitability phenotype.
SOD1
A4V/+
ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival
in vitro
when tested in
SOD1
mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.</abstract><pmid>24703839</pmid><doi>10.1016/j.celrep.2014.03.019</doi></addata></record> |
| fulltext | fulltext |
| identifier | EISSN: 2211-1247 |
| ispartof | Cell reports (Cambridge), 2014-04, Vol.7 (1), p.1-11 |
| issn | 2211-1247 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4023477 |
| source | DOAJ Directory of Open Access Journals; Cell Press Free Archives; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| title | Intrinsic Membrane Hyperexcitability of ALS Patient-Derived Motor Neurons |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-20T12%3A30%3A46IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmedcentral&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Intrinsic%20Membrane%20Hyperexcitability%20of%20ALS%20Patient-Derived%20Motor%20Neurons&rft.jtitle=Cell%20reports%20(Cambridge)&rft.au=Wainger,%20Brian%20J.&rft.date=2014-04-03&rft.volume=7&rft.issue=1&rft.spage=1&rft.epage=11&rft.pages=1-11&rft.eissn=2211-1247&rft_id=info:doi/10.1016/j.celrep.2014.03.019&rft_dat=%3Cpubmedcentral%3Epubmedcentral_primary_oai_pubmedcentral_nih_gov_4023477%3C/pubmedcentral%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/24703839&rfr_iscdi=true |