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Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import
Loss-of-function variants in NIMA-related kinase 1 (NEK1) constitute a major genetic cause of amyotrophic lateral sclerosis (ALS), accounting for 2 to 3% of all cases. However, how NEK1 mutations cause motor neuron (MN) dysfunction is unknown. Using mass spectrometry analyses for NEK1 interactors an...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10431718/ https://www.ncbi.nlm.nih.gov/pubmed/37585529 http://dx.doi.org/10.1126/sciadv.adi5548 |
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author | Mann, Jacob R. McKenna, Elizabeth D. Mawrie, Darilang Papakis, Vasileios Alessandrini, Francesco Anderson, Eric N. Mayers, Ryan Ball, Hannah E. Kaspi, Evan Lubinski, Katherine Baron, Desiree M. Tellez, Liana Landers, John E. Pandey, Udai B. Kiskinis, Evangelos |
author_facet | Mann, Jacob R. McKenna, Elizabeth D. Mawrie, Darilang Papakis, Vasileios Alessandrini, Francesco Anderson, Eric N. Mayers, Ryan Ball, Hannah E. Kaspi, Evan Lubinski, Katherine Baron, Desiree M. Tellez, Liana Landers, John E. Pandey, Udai B. Kiskinis, Evangelos |
author_sort | Mann, Jacob R. |
collection | PubMed |
description | Loss-of-function variants in NIMA-related kinase 1 (NEK1) constitute a major genetic cause of amyotrophic lateral sclerosis (ALS), accounting for 2 to 3% of all cases. However, how NEK1 mutations cause motor neuron (MN) dysfunction is unknown. Using mass spectrometry analyses for NEK1 interactors and NEK1-dependent expression changes, we find functional enrichment for proteins involved in the microtubule cytoskeleton and nucleocytoplasmic transport. We show that α-tubulin and importin-β1, two key proteins involved in these processes, are phosphorylated by NEK1 in vitro. NEK1 is essential for motor control and survival in Drosophila models in vivo, while using several induced pluripotent stem cell (iPSC)–MN models, including NEK1 knockdown, kinase inhibition, and a patient mutation, we find evidence for disruptions in microtubule homeostasis and nuclear import. Notably, stabilizing microtubules with two distinct classes of drugs restored NEK1-dependent deficits in both pathways. The capacity of NEK1 to modulate these processes that are critically involved in ALS pathophysiology renders this kinase a formidable therapeutic candidate. |
format | Online Article Text |
id | pubmed-10431718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-104317182023-08-17 Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import Mann, Jacob R. McKenna, Elizabeth D. Mawrie, Darilang Papakis, Vasileios Alessandrini, Francesco Anderson, Eric N. Mayers, Ryan Ball, Hannah E. Kaspi, Evan Lubinski, Katherine Baron, Desiree M. Tellez, Liana Landers, John E. Pandey, Udai B. Kiskinis, Evangelos Sci Adv Biomedicine and Life Sciences Loss-of-function variants in NIMA-related kinase 1 (NEK1) constitute a major genetic cause of amyotrophic lateral sclerosis (ALS), accounting for 2 to 3% of all cases. However, how NEK1 mutations cause motor neuron (MN) dysfunction is unknown. Using mass spectrometry analyses for NEK1 interactors and NEK1-dependent expression changes, we find functional enrichment for proteins involved in the microtubule cytoskeleton and nucleocytoplasmic transport. We show that α-tubulin and importin-β1, two key proteins involved in these processes, are phosphorylated by NEK1 in vitro. NEK1 is essential for motor control and survival in Drosophila models in vivo, while using several induced pluripotent stem cell (iPSC)–MN models, including NEK1 knockdown, kinase inhibition, and a patient mutation, we find evidence for disruptions in microtubule homeostasis and nuclear import. Notably, stabilizing microtubules with two distinct classes of drugs restored NEK1-dependent deficits in both pathways. The capacity of NEK1 to modulate these processes that are critically involved in ALS pathophysiology renders this kinase a formidable therapeutic candidate. American Association for the Advancement of Science 2023-08-16 /pmc/articles/PMC10431718/ /pubmed/37585529 http://dx.doi.org/10.1126/sciadv.adi5548 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Mann, Jacob R. McKenna, Elizabeth D. Mawrie, Darilang Papakis, Vasileios Alessandrini, Francesco Anderson, Eric N. Mayers, Ryan Ball, Hannah E. Kaspi, Evan Lubinski, Katherine Baron, Desiree M. Tellez, Liana Landers, John E. Pandey, Udai B. Kiskinis, Evangelos Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import |
title | Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import |
title_full | Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import |
title_fullStr | Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import |
title_full_unstemmed | Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import |
title_short | Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import |
title_sort | loss of function of the als-associated nek1 kinase disrupts microtubule homeostasis and nuclear import |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10431718/ https://www.ncbi.nlm.nih.gov/pubmed/37585529 http://dx.doi.org/10.1126/sciadv.adi5548 |
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