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Cited by 653Amyotrophic Lateral Sclerosis ResearchHereditary Neurological DisordersMuscle Physiology and Disorders

ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair

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Klim, Joseph R., Williams, Luis A., Limone, Francesco, Guerra San Juan, Irune, Davis-Dusenbery, Brandi N., Mordes, Daniel A., Burberry, Aaron, Steinbaugh, Michael J. +8 more·2019·Nature Neuroscience
DOI 10.1038/s41593-018-0300-4PMC PMC7153761
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Abstract

The findings that amyotrophic lateral sclerosis (ALS) patients almost universally display pathological mislocalization of the RNA-binding protein TDP-43 and that mutations in its gene cause familial ALS have nominated altered RNA metabolism as a disease mechanism. However, the RNAs regulated by TDP-43 in motor neurons and their connection to neuropathy remain to be identified. Here we report transcripts whose abundances in human motor neurons are sensitive to TDP-43 depletion. Notably, expression of STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown and TDP-43 mislocalization as well as in patient-specific motor neurons and postmortem patient spinal cord. STMN2 loss upon reduced TDP-43 function was due to altered splicing, which is functionally important, as we show STMN2 is necessary for normal axonal outgrowth and regeneration. Notably, post-translational stabilization of STMN2 rescued neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion. We propose that restoring STMN2 expression warrants examination as a therapeutic strategy for ALS.

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  • Pathological TDP-43 aggregation and premature polyadenylation and loss of stathmin-2 are pathologies commonly observed across sALS and fALS.

    “alternative approaches that mitigate pathologies commonly observed across sALS and fALS, such as pathological TDP-43 aggregation (39) or premature polyadenylation and loss of stathmin-2, a key regulator of microtubule dynamics in motor neurons (55, 56), are highly desirable.”

    From Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration (2023) · cites this paper as [56]

    The Results sections on postmortem ALS spinal cord and mutant TDP-43 motor neurons report reduced STMN2 in sporadic cases and in patient-derived motor neurons. The paper links STMN2 loss to cryptic-exon splicing, but the passages do not establish premature polyadenylation. Its Discussion also notes that FUS-mutant patients do not display TDP-43 pathology, so the claim's broad framing across sporadic and familial ALS needs qualification. TDP-43 aggregation is separately cited to reference 39 in the citing sentence. (LLM, conf=0.87)

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Authors
Klim, J. R., Williams, L. A., Limone, F., Guerra San Juan, I., Davis-Dusenbery, B. N., Mordes, D. A., Burberry, A., Steinbaugh, M. J., Gamage, K. K., Kirchner, R., Moccia, R., Cassel, S. H., Chen, K., Wainger, B. J., Woolf, C. J., & Eggan, K.
Affiliations
  • Broad Institute (US)
  • Harvard University (US)
  • Boston Children's Hospital (US)
Corresponding author
Eggan, Kevin
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2019-01-14
Volume
22
Issue
2
Pages
167-179
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-018-0300-4
PMC
PMC7153761
OpenAlex
W2907108807
Cited by
653
References
9
Citations by year
2026: 92 · 2025: 132 · 2024: 121 · 2023: 83 · 2022: 77 · 2021: 75 · 2020: 50 · 2019: 23
FWCI
38.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • VU Research Portal (publishedVersion, other-oa)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • Howard Hughes Medical Institute (NIH5R01NS089742)
  • Target ALS
  • National Institutes of Health (NIH5R01NS089742)
  • Harvard Stem Cell Institute
  • National Institute on Aging (R00AG057808, K99AG057808)
  • National Cancer Institute (T32CA009216)
  • National Institute of General Medical Sciences (T32GM007753)
  • National Institute of Neurological Disorders and Stroke (R01NS089742)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Keywords
amyotrophic lateral sclerosis, TDP-43, STMN2, motor neurons, RNA splicing, microtubule regulation, axon growth, axon regeneration, protein stabilization, RNA metabolism, TDP-43 mislocalization, pluripotent stem cells
MeSH terms
Amyotrophic Lateral Sclerosis, Axons, Cell Line, DNA-Binding Proteins, Female, Humans, Male, Membrane Proteins, Motor Neurons, Spinal Cord, Down-Regulation, Stathmin, Induced Pluripotent Stem Cells

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