An acetylation switch controls TDP-43 function and aggregation propensity

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

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

Substances

  • DNA Primers
  • DNA-Binding Proteins
  • RNA, Small Interfering
  • Recombinant Proteins
  • TARDBP protein, human
  • Lysine