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 and Virginia M. Y. Lee
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Todd J. Cohen: UNC Neuroscience Center, University of North Carolina at Chapel Hill, 115 Mason Farm Road, NRB 6109A, CB #7250
Andrew W. Hwang: Institute on Aging and Center for Neurodegenerative Disease Research, 3600 Spruce Street, 3rd Fl Maloney Building
Clark R. Restrepo: Institute on Aging and Center for Neurodegenerative Disease Research, 3600 Spruce Street, 3rd Fl Maloney Building
Chao-Xing Yuan: University of Pennsylvania School of Medicine, 838 Biomedical Research Building II/III, 421 Curie Boulevard
John Q. Trojanowski: Institute on Aging and Center for Neurodegenerative Disease Research, 3600 Spruce Street, 3rd Fl Maloney Building
Virginia M. Y. Lee: Institute on Aging and Center for Neurodegenerative Disease Research, 3600 Spruce Street, 3rd Fl Maloney Building

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms6845

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