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Cited by 635Amyotrophic Lateral Sclerosis ResearchRNA Research and SplicingHereditary Neurological Disorders

Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration

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Melamed, Ze’ev, López-Erauskin, Jone, Baughn, Michael W., Zhang, Ouyang, Drenner, Kevin, Sun, Ying, Freyermuth, Fernande, McMahon, Moira A. +12 more·2019·Nature Neuroscience
DOI 10.1038/s41593-018-0293-zPMC PMC6348009
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Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with loss of nuclear transactive response DNA-binding protein 43 (TDP-43). Here we identify that TDP-43 regulates expression of the neuronal growth-associated factor stathmin-2. Lowered TDP-43 levels, which reduce its binding to sites within the first intron of stathmin-2 pre-messenger RNA, uncover a cryptic polyadenylation site whose utilization produces a truncated, non-functional mRNA. Reduced stathmin-2 expression is found in neurons trans-differentiated from patient fibroblasts expressing an ALS-causing TDP-43 mutation, in motor cortex and spinal motor neurons from patients with sporadic ALS and familial ALS with GGGGCC repeat expansion in the C9orf72 gene, and in induced pluripotent stem cell (iPSC)-derived motor neurons depleted of TDP-43. Remarkably, while reduction in TDP-43 is shown to inhibit axonal regeneration of iPSC-derived motor neurons, rescue of stathmin-2 expression restores axonal regenerative capacity. Thus, premature polyadenylation-mediated reduction in stathmin-2 is a hallmark of ALS-FTD that functionally links reduced nuclear TDP-43 function to enhanced neuronal vulnerability.

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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 [55]

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Authors
Melamed, Z., López-Erauskin, J., Baughn, M. W., Zhang, O., Drenner, K., Sun, Y., Freyermuth, F., McMahon, M. A., Beccari, M. S., Artates, J. W., Ohkubo, T., Rodriguez, M., Lin, N., Wu, D., Bennett, C. F., Rigo, F., Da Cruz, S., Ravits, J., Lagier-Tourenne, C., & Cleveland, D. W.
Affiliations
  • University of California San Diego (US)
  • Broad Institute (US)
  • Ionis Pharmaceuticals (United States) (US)
Corresponding author
Cleveland, Don W.
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2019-01-14
Volume
22
Issue
2
Pages
180-190
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-018-0293-z
PMC
PMC6348009
OpenAlex
W2910480975
Cited by
635
References
10
Citations by year
2026: 83 · 2025: 124 · 2024: 127 · 2023: 90 · 2022: 68 · 2021: 78 · 2020: 44 · 2019: 21
FWCI
35.70
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institute of General Medical Sciences (T32GM008666)
  • National Institute of Neurological Disorders and Stroke (R01NS087227, P30NS047101, R01NS088578, R01NS027036)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
TDP-43, STMN2, amyotrophic lateral sclerosis, frontotemporal dementia, C9orf72 repeat expansion, motor neurons, axon regeneration, alternative splicing, TDP-43 mutations, iPSC-derived motor neurons, neuronal vulnerability
MeSH terms
Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Female, Humans, Membrane Proteins, Motor Cortex, Motor Neurons, Nerve Degeneration, Spinal Cord, Polyadenylation, Stathmin

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