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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
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.
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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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