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Publication Detail

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

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

Published In Nat Commun, (2015)

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.

PubMed ID: 25556531 Exiting the NIEHS site

MeSH Terms: Acetylation; Amyotrophic Lateral Sclerosis/metabolism*; Amyotrophic Lateral Sclerosis/pathology; Cloning, Molecular; DNA Primers/genetics; DNA-Binding Proteins/metabolism*; Frontotemporal Lobar Degeneration/metabolism*; Humans; Immunohistochemistry; Immunoprecipitation; Lysine/metabolism*; Mass Spectrometry; Mutagenesis, Site-Directed; Oxidative Stress/physiology; Protein Aggregation, Pathological/genetics; Protein Aggregation, Pathological/metabolism*; RNA, Small Interfering/genetics; Recombinant Proteins/metabolism*; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord/pathology

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