Rapamycin Rescues TDP-43 Mislocalization and the Associated Low Molecular Mass Neurofilament Instability
Open accessAbstract
TDP-43 is a nuclear protein involved in exon skipping and alternative splicing. Recently, TDP-43 has been identified as the pathological signature protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. In addition, TDP-43-positive inclusions are present in Parkinson disease, dementia with Lewy bodies, and 30% of Alzheimer disease cases. Pathological TDP-43 is redistributed from the nucleus to the cytoplasm, where it accumulates. An approximately 25-kDa C-terminal fragment of TDP-43 accumulates in affected brain regions, suggesting that it may be involved in the disease pathogenesis. Here, we show that overexpression of the 25-kDa C-terminal fragment is sufficient to cause the mislocalization and cytoplasmic accumulation of endogenous full-length TDP-43 in two different cell lines, thus recapitulating a key biochemical characteristic of TDP-43 proteinopathies. We also found that TDP-43 mislocalization is associated with a reduction in the low molecular mass neurofilament mRNA levels. Notably, we show that the autophagic system plays a role in TDP-43 metabolism. Specifically, we found that autophagy inhibition increases the accumulation of the C-terminal fragments of TDP-43, whereas inhibition of mTOR, a key protein kinase involved in autophagy regulation, reduces the 25-kDa C-terminal fragment accumulation and restores TDP-43 localization. Our results suggest that autophagy induction may be a valid therapeutic target for TDP-43 proteinopathies.
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Inhibiting autophagy with 3-methyladenine impairs TARDBP degradation.
“inhibiting autophagy with 3-methyladenine impairs TARDBP degradation [352].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [352]
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 [352]
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Self-citation
- Authors
- Caccamo, A., Majumder, S., Deng, J. J., Bai, Y., Thornton, F. B., & Oddo, S.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Oddo, Salvatore
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 284
- Issue
- 40
- Pages
- 27416-27424
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2785671
- OpenAlex
- W1996815931
- Cited by
- 169
- References
- 57
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 3 · 2023: 9 · 2022: 7 · 2021: 10 · 2020: 10 · 2019: 5 · 2018: 10 · 2017: 5 · 2016: 10 · 2015: 7 · 2014: 16 · 2013: 13 · 2012: 14
- FWCI
- 9.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Strong
- 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, TDP-43 mislocalization, autophagy, mTOR, rapamycin, TDP-43 proteinopathy, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, therapeutic target
- MeSH terms
- Amino Acid Sequence, Animals, Autophagy, Cytoplasm, DNA-Binding Proteins, Gene Expression Regulation, Humans, Molecular Sequence Data, Molecular Weight, RNA, Messenger, Neurofilament Proteins, Sirolimus, Protein Transport, Cell Line, Tumor, Mice, Protein Stability
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