TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration
Open accessAbstract
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that show considerable clinical and pathologic overlap, with no effective treatments available. Mutations in the RNA binding protein TDP-43 were recently identified in patients with familial amyotrophic lateral sclerosis (ALS), and TDP-43 aggregates are found in both ALS and FTLD-U (FTLD with ubiquitin aggregates), suggesting a common underlying mechanism. We report that mice expressing a mutant form of human TDP-43 develop a progressive and fatal neurodegenerative disease reminiscent of both ALS and FTLD-U. Despite universal transgene expression throughout the nervous system, pathologic aggregates of ubiquitinated proteins accumulate only in specific neuronal populations, including layer 5 pyramidal neurons in frontal cortex, as well as spinal motor neurons, recapitulating the phenomenon of selective vulnerability seen in patients with FTLD-U and ALS. Surprisingly, cytoplasmic TDP-43 aggregates are not present, and hence are not required for TDP-43-induced neurodegeneration. These results indicate that the cellular and molecular substrates for selective vulnerability in FTLD-U and ALS are shared between mice and humans, and suggest that altered DNA/RNA-binding protein function, rather than toxic aggregation, is central to TDP-43-related neurodegeneration.
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In TDP-43 mouse models, pathogenesis involves a combination of loss of nuclear TDP43 function and TDP-43 cytoplasmic gain-of-toxic-function.
“In TDP-43 mouse models, pathogenesis is involved in a combination of loss of nuclear TDP43 function and TDP-43 cytoplasmic gain-of-toxic-function.334”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [334]
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“To test this, 156 we crossed two independent Nlk gene trap loss-of-function mouse lines (NlkXN619/+ and NlkRRJ297/+) 157 (7, 8), collectively referred to here as Nlk+/-, with transgenic mice expressing a fALS-causing 158 mutant hTARDBPA315T under the control of a Prp promoter (28), referred to here as Prp-TDPA315T/+.”
Method
- Authors
- Wegorzewska, I., Bell, S., Cairns, N. J., Miller, T. M., & Baloh, R. H.
- Affiliations
- Department of Neurology and
- Washington University in St. Louis (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-11-03
- Volume
- 106
- Issue
- 44
- Pages
- 18809-18814
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2762420
- OpenAlex
- W2072413533
- Cited by
- 706
- References
- 31
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 30 · 2023: 35 · 2022: 31 · 2021: 51 · 2020: 51 · 2019: 30 · 2018: 41 · 2017: 30 · 2016: 31 · 2015: 41 · 2014: 45 · 2013: 49 · 2012: 58
- FWCI
- 41.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Burroughs Wellcome Fund
- Muscular Dystrophy Association
- Children's Discovery Institute
- Hope Center for Neurological Disorders
- National Institutes of Health (NS057105)
- National Institute of Neurological Disorders and Stroke (NS055980, P30NS057105, NS057105, K08NS055980)
- 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 › Hereditary Neurological Disorders
- Keywords
- TDP-43, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, FTLD-U, transgenic mice, TDP-43 mutations, protein aggregation, selective neuronal vulnerability, layer 5 pyramidal neurons, spinal motoneurons, RNA-binding proteins, neurodegeneration
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Brain, Disease Models, Animal, DNA-Binding Proteins, Gait, Humans, Mice, Transgenic, Mutation, Survival Analysis, Mice, Frontotemporal Lobar Degeneration
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