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

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

Author information

1
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.
2
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.
3
Department of Pharmacology, University of Pennsylvania School of Medicine, 838 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.

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.

PMID:
25556531
PMCID:
PMC4407365
DOI:
10.1038/ncomms6845
[Indexed for MEDLINE]
Free PMC Article

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