An acetylation switch controls TDP-43 function and aggregation propensity

Todd J. Cohen, Andrew W. Hwang, Clark R. Restrepo, Chao Xing Yuan, John Q. Trojanowski, Virginia M.Y. Lee

Research output: Research - peer-reviewArticle

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Abstract

TDP-43 pathology is a disease hallmark that characterizes amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). Although a critical role for TDP-43 as an RNA-binding protein has emerged, the regulation of TDP-43 function is poorly understood. Here, we identify lysine acetylation as a novel post-translational modification controlling TDP-43 function and aggregation. We provide evidence that TDP-43 acetylation impairs RNA binding and promotes accumulation of insoluble, hyper-phosphorylated TDP-43 species that largely resemble pathological inclusions in ALS and FTLD-TDP. Moreover, biochemical and cell-based assays identify oxidative stress as a signalling cue that promotes acetylated TDP-43 aggregates that are readily engaged by the cellular defense machinery. Importantly, acetylated TDP-43 lesions are found in ALS patient spinal cord, indicating that aberrant TDP-43 acetylation and loss of RNA binding are linked to TDP-43 proteinopathy. Thus, modulating TDP-43 acetylation represents a plausible strategy to fine-tune TDP-43 activity, which could provide new therapeutic avenues for TDP-43 proteinopathies.

LanguageEnglish (US)
Article number5845
JournalNature Communications
Volume6
DOIs
StatePublished - Jan 5 2015

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Acetylation
Agglomeration
Switches
acetylation
switches
Amyotrophic Lateral Sclerosis
TDP-43 Proteinopathies
Frontotemporal Dementia
RNA
Frontotemporal Lobar Degeneration
RNA-Binding Proteins
Post Translational Protein Processing
Lysine
Cues
Spinal Cord
Oxidative Stress
Pathology
Therapeutics
Oxidative stress
Machinery

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Cohen, T. J., Hwang, A. W., Restrepo, C. R., Yuan, C. X., Trojanowski, J. Q., & Lee, V. M. Y. (2015). An acetylation switch controls TDP-43 function and aggregation propensity. Nature Communications, 6, [5845]. DOI: 10.1038/ncomms6845

An acetylation switch controls TDP-43 function and aggregation propensity. / Cohen, Todd J.; Hwang, Andrew W.; Restrepo, Clark R.; Yuan, Chao Xing; Trojanowski, John Q.; Lee, Virginia M.Y.

In: Nature Communications, Vol. 6, 5845, 05.01.2015.

Research output: Research - peer-reviewArticle

Cohen, TJ, Hwang, AW, Restrepo, CR, Yuan, CX, Trojanowski, JQ & Lee, VMY 2015, 'An acetylation switch controls TDP-43 function and aggregation propensity' Nature Communications, vol 6, 5845. DOI: 10.1038/ncomms6845
Cohen TJ, Hwang AW, Restrepo CR, Yuan CX, Trojanowski JQ, Lee VMY. An acetylation switch controls TDP-43 function and aggregation propensity. Nature Communications. 2015 Jan 5;6. 5845. Available from, DOI: 10.1038/ncomms6845
Cohen, Todd J. ; Hwang, Andrew W. ; Restrepo, Clark R. ; Yuan, Chao Xing ; Trojanowski, John Q. ; Lee, Virginia M.Y./ An acetylation switch controls TDP-43 function and aggregation propensity. In: Nature Communications. 2015 ; Vol. 6.
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