Cytoplasmic Mislocalization of TDP-43 Is Toxic to Neurons and Enhanced by a Mutation Associated with Familial Amyotrophic Lateral Sclerosis
Open accessAbstract
Mutations in the gene encoding TDP-43—the major protein component of neuronal aggregates characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusion bodies—have been linked to familial forms of both disorders. Aggregates of TDP-43 in cortical and spinal motorneurons in ALS, or in neurons of the frontal and temporal cortices in FTLD, are closely linked to neuron loss and atrophy in these areas. However, the mechanism by which TDP-43 mutations lead to neurodegeneration is unclear. To investigate the pathogenic role of TDP-43 mutations, we established a model of TDP-43 proteinopathies by expressing fluorescently tagged wild-type and mutant TDP-43 in primary rat cortical neurons. Expression of mutant TDP-43 was toxic to neurons, and mutant-specific toxicity was associated with increased cytoplasmic mislocalization of TDP-43. Inclusion bodies were not necessary for the toxicity and did not affect the risk of cell death. Cellular survival was unaffected by the total amount of exogenous TDP-43 in the nucleus, but the amount of cytoplasmic TDP-43 was a strong and independent predictor of neuronal death. These results suggest that mutant TDP-43 is mislocalized to the cytoplasm, where it exhibits a toxic gain-of-function and induces cell death.
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Accumulation of insoluble mutant TARDBP has been closely linked to neurodegeneration.
“which in previous models has not only been closely linked to neurodegeneration [297]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [297]
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Self-citation
- Authors
- Barmada, S. J., Skibinski, G., Korb, E., Rao, E. J., Wu, J. Y., & Finkbeiner, S.
- Affiliations
- Gladstone Institutes (US)
- Northwestern University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-01-13
- Volume
- 30
- Issue
- 2
- Pages
- 639-649
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2821110
- OpenAlex
- W2028611597
- Cited by
- 554
- References
- 41
- Citations by year
- 2026: 27 · 2025: 42 · 2024: 42 · 2023: 35 · 2022: 33 · 2021: 46 · 2020: 53 · 2019: 36 · 2018: 31 · 2017: 22 · 2016: 22 · 2015: 18 · 2014: 28 · 2013: 31 · 2012: 32
- FWCI
- 22.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Gladstone Institutes
- National Institutes of Health (1c06rr018928-01, AG‐022074)
- National Institute on Aging (P01AG022074)
- National Eye Institute (R01EY014576, EY014576)
- National Institute of General Medical Sciences (R01GM070967, GM070967)
- National Institute of Neurological Disorders and Stroke (R01NS039074)
- National Center for Research Resources (C06-RR-018928)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- TDP-43, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, cytoplasmic mislocalization, gain-of-function toxicity, neuronal cell death, TDP-43 mutations, proteinopathies, cortical neurons, neurodegeneration
- MeSH terms
- Animals, Cell Survival, Cells, Cultured, Cerebral Cortex, DNA-Binding Proteins, Embryo, Mammalian, Glycine, Humans, Image Processing, Computer-Assisted, Microscopy, Fluorescence, Mutation, Neurons, Predictive Value of Tests, Subcellular Fractions, Time Factors, Transfection, Proportional Hazards Models, Mutagenesis, Site-Directed, Protein Transport, Green Fluorescent Proteins, Rats, Kaplan-Meier Estimate
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