Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS

Michael E. Bekier II; Emile S. Pinarbasi; Gopinath Krishnan; Jack J. Mesojedec; Madelaine Hurley; Harisankar Harikumar Sheela; Catherine A. Collins; Layla T. Ghaffari; Martina de Majo; Erik M. Ullian; Mark Koontz; Sarah Coleman; Xingli Li; Elizabeth M.H. Tank; Jacob Waksmacki; Fen-Biao Gao; Sami J. Barmada

doi:10.1172/JCI188138

¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

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¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

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¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

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¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

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¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

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¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

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¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

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¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

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¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

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¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

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¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

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¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

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¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

Find articles by Li, X. in: PubMed | Google Scholar

¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

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¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

Find articles by Waksmacki, J. in: PubMed | Google Scholar

¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

Find articles by Gao, F. in: PubMed | Google Scholar

¹Department of Neurology, University of Michigan, Ann Arbor, United States of America

²Department of Pathology, University of Michigan, Ann Arbor, United States of America

³Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States of America

⁴Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

⁵Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, United States of America

⁶Synapticure, Chicago, United States of America

⁷Department of Ophthalmology, UCSF, San Francisco, United States of America

Find articles by Barmada, S. in: PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI188138.
Copyright © 2025, Bekier II et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 24, 2025 - Version history

Cytoplasmic TDP43 mislocalization and aggregation are pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the initial cellular insults that lead to TDP43 mislocalization remain unclear. In this study, we demonstrate that Nemo-like kinase (NLK) — a proline-directed serine/threonine kinase — promotes the mislocalization of TDP43 and other RNA-binding proteins by disrupting nuclear import. NLK levels are selectively elevated in neurons exhibiting TDP43 mislocalization in ALS patient tissues, while genetic reduction of NLK reduces toxicity in human neuron models of ALS. Our findings suggest that NLK is a promising therapeutic target for neurodegenerative diseases.

Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS

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Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS

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