Evidence map›Paper›PMID 40553568›Full record

ArticleThe Journal of clinical investigation2025

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

Michael E Bekier, Emile Pinarbasi, Gopinath Krishnan, Jack J Mesojedec, Madelaine Hurley, Harisankar Harikumar Sheela, Catherine A Collins, Layla Ghaffari, Martina de Majo, Erik M Ullian and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

17 authors.

Michael E BekierDepartment of Neurology and.
Emile PinarbasiDepartment of Neurology and.
Gopinath KrishnanFrontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
Jack J MesojedecDepartment of Neurology and.
Madelaine HurleyDepartment of Neurology and.
Harisankar Harikumar SheelaDepartment of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
Catherine A CollinsDepartment of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Layla GhaffariSynapticure, Chicago, Illinois, USA.
Martina de MajoSynapticure, Chicago, Illinois, USA.
Erik M UllianDepartment of Ophthalmology, University of California, San Francisco, San Francisco, California, USA.
Mark KoontzSynapticure, Chicago, Illinois, USA.
Sarah ColemanSynapticure, Chicago, Illinois, USA.
Xingli LiDepartment of Neurology and.
Elizabeth Mh TankDepartment of Neurology and.
Jacob WaksmackiDepartment of Neurology and.
Fen-Biao GaoFrontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
Sami J BarmadaDepartment of Neurology and.

Funding

Michigan Institute for Clinical and Health Research (MCHR)UL1TR000433 · NCATS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI MASHOUR, GEORGE ALEXANDER · 2012 to 2016
$49.9M
Research Education ComponentP30AG072931 · NIA · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Henry L Paulson · 2021 to 2026
$26.5M
Regenerative and Degenerative Responses to Axonal InjuryR01NS069844 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CADIGAN, KENNETH M, COLLINS, CATHERINE A · 2010 to 2024
$5.0M
Investigating Pathogenic Mechanisms of Frontotemporal Dementia Caused by Mutations in CHMP2B and TBK1R37NS057553 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI GAO, FEN-BIAO · 2018 to 2024
$4.3M
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degenerationR01NS097542 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BARMADA, SAMI · 2016 to 2025
$3.8M
Novel patient-derived 3D platform for detecting TDP-43 proteinopathy and associated biomarkers for ALS/FTDR44NS124457 · NINDS · SYNAPTICURE, INC. · PI GHAFFARI, LAYLA, ULLIAN, ERIK M · 2022 to 2023
$2.2M
Atypical TDP43 isoforrms driving neurodegeneration in FTD/ALSR01NS113943 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BARMADA, SAMI · 2020 to 2024
$1.9M
Regenerative and degenerative responses to axonal injuryR56NS069844 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI COLLINS, CATHERINE A · 2020 to 2020
$546k
Spatiotemporal analysis of TDP-43 toxicity and endolysosomal turnover mechanismsR56NS128110 · NINDS · UNIVERSITY OF ARIZONA · PI BARMADA, SAMI, BUCHAN, JOHN ROSS · 2022 to 2022
$393k
NCATS NIH HHS UL1 TR000433NIA NIH HHS P30 AG072931NINDS NIH HHS R01 NS069844NINDS NIH HHS R01 NS097542NINDS NIH HHS R01 NS113943NINDS NIH HHS R37 NS057553NINDS NIH HHS R44 NS124457NINDS NIH HHS R56 NS069844NINDS NIH HHS R56 NS128110
6 · The paper itself

Abstract

Cytoplasmic transactive response DNA-binding protein 43 (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 were selectively elevated in neurons exhibiting TDP43 mislocalization in tissues from patients with ALS, and genetic reduction of NLK reduced toxicity in human neuron models of ALS. Our findings suggest that NLK is a promising therapeutic target for neurodegenerative diseases.

Indexed as

Amyotrophic Lateral SclerosisCell NucleusDNA-Binding ProteinsIntracellular Signaling Peptides and ProteinsProtein Serine-Threonine KinasesActive Transport, Cell NucleusAnimalsHumansMiceNeuronsDNA-Binding ProteinsIntracellular Signaling Peptides and ProteinsNLK protein, humanProtein Serine-Threonine KinasesTARDBP protein, humanALSCell biologyMolecular pathologyNeuroscienceTransport

Identifiers

PMID40553568
PMCPMC12404744

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.