Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability

Antonella Caccamo, Smita Majumder, Janice J. Deng, Yidong Bai, Fiona B. Thornton, Salvatore Oddo

Research output: Contribution to journalArticle

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Abstract

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 ∼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.

Original languageEnglish (US)
Pages (from-to)27416-27424
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number40
DOIs
StatePublished - Oct 2 2009
Externally publishedYes

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TDP-43 Proteinopathies
Intermediate Filaments
Autophagy
Molecular mass
Sirolimus
Enzyme inhibition
Lewy Body Disease
Frontotemporal Dementia
Amyotrophic Lateral Sclerosis
Alternative Splicing
Nuclear Proteins
Ubiquitin
Metabolism
Protein Kinases
Parkinson Disease
Exons
Brain
Alzheimer Disease
Cytoplasm
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. / Caccamo, Antonella; Majumder, Smita; Deng, Janice J.; Bai, Yidong; Thornton, Fiona B.; Oddo, Salvatore.

In: Journal of Biological Chemistry, Vol. 284, No. 40, 02.10.2009, p. 27416-27424.

Research output: Contribution to journalArticle

Caccamo, Antonella ; Majumder, Smita ; Deng, Janice J. ; Bai, Yidong ; Thornton, Fiona B. ; Oddo, Salvatore. / Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 40. pp. 27416-27424.
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