Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43
Open accessAbstract
TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies.
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Inhibition of MTOR reduces TARDBP aggregation and toxicity in multiple cell and animal models of ALS.
“Inhibition of MTOR likewise reduces TARDBP aggregation and toxicity in multiple cell and animal models of ALS [353,358,359].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [353]
Inducing autophagy with rapamycin reduces TARDBP accumulation and mislocalization in vitro and in vivo.
“inducing autophagy with rapamycin reduces TARDBP accumulation and mislocalization in vitro [352] and in vivo [353]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [353]
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“Because soluble and aggregated forms of TDP-43 and its cleavage products can be cleared through the ALP (27–30), we aimed to determine whether TDP-43 levels could be modulated through altering Nlk levels.”
- Authors
- Wang, I.-F., Guo, B.-S., Liu, Y.-C., Wu, C.-C., Yang, C.-H., Tsai, K.-J., & Shen, C.-K. J.
- Affiliations
- Institute of Molecular Biology, Academia Sinica (TW)
- National Cheng Kung University (TW)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-08-29
- Volume
- 109
- Issue
- 37
- Pages
- 15024-15029
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3443184
- OpenAlex
- W2111425566
- Cited by
- 377
- References
- 37
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 22 · 2023: 13 · 2022: 23 · 2021: 37 · 2020: 37 · 2019: 29 · 2018: 37 · 2017: 31 · 2016: 22 · 2015: 39 · 2014: 34 · 2013: 27 · 2012: 2
- FWCI
- 21.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- TDP-43, FTLD-U, amyotrophic lateral sclerosis, autophagy, rapamycin, mTOR, spermidine, carbamazepine, tamoxifen, ubiquitin-positive inclusions, neurodegeneration, motor impairment, learning and memory impairment, caspase-3, p70 S6 kinase, p62, LC3, neuroprotection
- MeSH terms
- Analysis of Variance, Animals, Autophagy, Carbamazepine, Fluorometry, Memory Disorders, Psychomotor Performance, Spermidine, Tamoxifen, Blotting, Western, Maze Learning, Sirolimus, In Situ Nick-End Labeling, Rotarod Performance Test, Mice, Caspase 3, TDP-43 Proteinopathies, Frontotemporal Dementia, TOR Serine-Threonine Kinases
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