Reduced protein turnover mediates functional deficits in transgenic mice expressing the 25 kDa C-terminal fragment of TDP-43
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) are two neurodegenerative disorders characterized by the accumulation of TDP-43. TDP-43 is proteolitically cleaved to generate two major C-terminal fragments of 35 and 25 kDa. The latter, known as TDP-25, is a consistent feature of FTLD-TDP and ALS; however, little is known about its role in disease pathogenesis. We have previously developed transgenic mice overexpressing low levels of TDP-25 (TgTDP-25(+/0)), which at 6 months of age show mild cognitive impairments and no motor deficits. To better understand the role of TDP-25 in the pathogenesis of ALS and FTLD-TDP, we generated TDP-25 homozygous mice (TgTDP-25(+/+)), thereby further increasing TDP-25 expression. We found a gene-dosage effect on cognitive and motor function at 15 months of age, as the TgTDP-25(+/+) showed more severe spatial and working memory deficits as well as worse motor performance than TgTDP-25(+/0) mice. These behavioral deficits were associated with increased soluble levels of TDP-25 in the nucleus and cytosol. Notably, high TDP-25 levels were also linked to reduced autophagy induction and proteasome function, two events that have been associated with both ALS and FTLD-TDP. In summary, we present strong in vivo evidence that high levels of TDP-25 are sufficient to cause behavioral deficits and reduce function of two of the major protein turnover systems: autophagy and proteasome. These mice represent a new tool to study the role of TDP-25 in the pathogenesis of ALS and FTLD-TDP.
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Autophagy dysfunction is linked to TARDBP pathology in ALS.
“Together, these findings link autophagy dysfunction to TARDBP pathology in ALS”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [351]
Transgenic expression of a C-terminal TARDBP fragment commonly associated with ALS and FTD leads to decreases in several autophagy effectors, including ATG3, ATG7, LC3, SQSTM1, and BECN1.
“Transgenic expression of a C-terminal TARDBP fragment commonly associated with ALS and FTD leads to decreases in several autophagy effectors, including ATG3, ATG7, LC3, SQSTM1, and BECN1 [351].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [351]
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Autophagy and ALS: mechanistic insights and therapeutic implications
Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J. (2022) · Autophagy · doi:10.1080/15548627.2021.1926656 · Cited by 189 · see citing works
- Authors
- Caccamo, A., Shaw, D. M., Guarino, F., Messina, A., Walker, A. W., & Oddo, S.
- Affiliations
- University of Catania (IT)
- Banner Sun Health Research Institute (US)
- Corresponding author
- Oddo, Salvatore
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-05-22
- Volume
- 24
- Issue
- 16
- Pages
- 4625-4635
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2133613163
- Cited by
- 35
- References
- 49
- Citations by year
- 2024: 2 · 2023: 1 · 2022: 7 · 2021: 6 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 6 · 2016: 1 · 2015: 2 · 2014: 1
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- 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, protein turnover, autophagy, proteasome, cognitive impairment, motor impairment, gene dosage effect, transgenic mouse model, neurodegeneration
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Autophagy, Behavior, Animal, DNA-Binding Proteins, Humans, Mice, Transgenic, Protein Structure, Tertiary, Proteasome Endopeptidase Complex, Mice, Frontotemporal Lobar Degeneration, Proteolysis
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