Send to

Choose Destination
Nat Commun. 2015 Jan 5;6:5845. doi: 10.1038/ncomms6845.

An acetylation switch controls TDP-43 function and aggregation propensity.

Author information

Department of Neurology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, 115 Mason Farm Road, NRB 6109A, CB #7250, Chapel Hill, North Carolina 27599, USA.
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, 3600 Spruce Street, 3rd Fl Maloney Building, Philadelphia Pennsylvania 19104, USA.
Department of Pharmacology, University of Pennsylvania School of Medicine, 838 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center