The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability
Open accessAbstract
Transactive response DNA-binding (TDP-43) protein is the dominant disease protein in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP). Identification of mutations in the gene encoding TDP-43 ( TARDBP ) in familial ALS confirms a mechanistic link between misaccumulation of TDP-43 and neurodegeneration and provides an opportunity to study TDP-43 proteinopathies in human neurons generated from patient fibroblasts by using induced pluripotent stem cells (iPSCs). Here, we report the generation of iPSCs that carry the TDP-43 M337V mutation and their differentiation into neurons and functional motor neurons. Mutant neurons had elevated levels of soluble and detergent-resistant TDP-43 protein, decreased survival in longitudinal studies, and increased vulnerability to antagonism of the PI3K pathway. We conclude that expression of physiological levels of TDP-43 in human neurons is sufficient to reveal a mutation-specific cell-autonomous phenotype and strongly supports this approach for the study of disease mechanisms and for drug screening.
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“Familial ALS patient iPSC-derived motor neurons with TDP-43 mutation showed decreased voltage-activated Na+ and K+ currents and increased vulnerability [39].”
From Utility of iPSC-Derived Cells for Disease Modeling, Drug Development, and Cell Therapy (2022) · cites this paper as [39]
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“iPSC-derived motor neurons harboring the ALS-associated TARDBPM337V mutation demonstrate an accumulation of insoluble mutant TARDBP at native expression levels [298]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [298]
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Cites
Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors
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Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells
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Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
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Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling
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TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., et al. (2008) · Science · doi:10.1126/science.1154584 · Cited by 2,630
Self-citationReprogramming of human somatic cells to pluripotency with defined factors
Park, I.-H., Zhao, R., West, J. A., Yabuuchi, A., Huo, H., Ince, T. A., Lerou, P. H., Lensch, M. W., & Daley, G. Q. (2008) · Nature · doi:10.1038/nature06534 · Cited by 2,436
Self-citationDimos, J. T., Rodolfa, K. T., Niakan, K. K., Weisenthal, L. M., Mitsumoto, H., Chung, W. K., Croft, G. F., Saphier, G., Leibel, R. L., Goland, R., et al. (2008) · Science · doi:10.1126/science.1158799 · Cited by 2,019
Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death
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Self-citationDirected differentiation of embryonic stem cells into motor neurons.
Wichterle, H., Lieberam, I., Porter, J. A., & Jessell, T. (2002) · Cell · doi:10.1016/s0092-8674(02)00835-8 · Cited by 1,792
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Miller, J. D., Ganat, Y. M., Kishinevsky, S., Bowman, R. L., Liu, B., Tu, E. Y., Mandal, P. K., Vera, E., Shim, J.-W., Kriks, S., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.11.006 · Cited by 777
ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?
Mejzini, R., Flynn, L. L., Pitout, I. L., Fletcher, S., Wilton, S. D., & Akkari, P. A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01310 · Cited by 803
Axonal Transport of TDP-43 mRNA Granules Is Impaired by ALS-Causing Mutations
Alami, N. H., Smith, R. B., Carrasco, M. A., Williams, L. A., Winborn, C. S., Han, S. S. W., Kiskinis, E., Winborn, B., Freibaum, B. D., Kanagaraj, A., et al. (2014) · Neuron · doi:10.1016/j.neuron.2013.12.018 · Cited by 660
Self-citationALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair
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., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0300-4 · Cited by 653
Protein aggregation in amyotrophic lateral sclerosis
Blokhuis, A. M., Groen, E. J. N., Koppers, M., van den Berg, L. H., & Pasterkamp, R. J. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1125-6 · Cited by 607
Metadata
- Authors
- Bilican, B., Serio, A., Barmada, S. J., Nishimura, A. L., Sullivan, G. J., Carrasco, M., Phatnani, H. P., Puddifoot, C. A., Story, D., Fletcher, J., Park, I.-H., Friedman, B. A., Daley, G. Q., Wyllie, D. J. A., Hardingham, G. E., Wilmut, I., Finkbeiner, S., Maniatis, T., Shaw, C. E., & Chandran, S.
- Affiliations
- MRC Centre for Regenerative Medicine (GB)
- Gladstone Institutes (US)
- King's College London (GB)
- Department of Biochemistry and Molecular Biophysics,Columbia University, New York, NY 10032;
- Columbia University (US)
- University of Edinburgh (GB)
- Yale University (US)
- Harvard University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-03-26
- Volume
- 109
- Issue
- 15
- Pages
- 5803-5808
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3326463
- OpenAlex
- W2131321387
- Cited by
- 328
- References
- 51
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 9 · 2023: 13 · 2022: 15 · 2021: 15 · 2020: 15 · 2019: 22 · 2018: 20 · 2017: 21 · 2016: 43 · 2015: 38 · 2014: 37 · 2013: 45 · 2012: 18
- FWCI
- 28.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- Funders
- Wellcome Trust (089701)
- Motor Neurone Disease Association (CHANDRAN/MAR10/982-797, Chandran/Mar10/6751)
- Medical Research Council (MC_G1000733)
- Biotechnology and Biological Sciences Research Council
- National Institute of Neurological Disorders and Stroke (K08NS072233, R01NS039074)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- TDP-43, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, TARDBP, induced pluripotent stem cells, iPSC-derived neurons, motor neurons, PI3K signaling, neurodegeneration, drug screening
- MeSH terms
- Adult, Cell Differentiation, Detergents, DNA-Binding Proteins, Female, Fibroblasts, Humans, Male, Middle Aged, Motor Neurons, Mutation, Organ Specificity, Solubility, Induced Pluripotent Stem Cells, TDP-43 Proteinopathies
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