TDP-43 acetylation as a pathogenic modification in ALS & related proteinopathies

Project: Research project


Project Summary/Abstract

Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron disease with a 3-5 year survival rate and no disease-modifying therapies. TAR DNA-binding protein of 43kD (TDP-43) is a nuclear RNA and DNA binding protein that becomes abnormally aggregated in the brain and spinal cord of most ALS patients as well as a subset of dementia patients (frontotemporal lobar degeneration with TDP-43 pathology, or FTLD-TDP), placing ALS and FTLD-TDP within a spectrum of diseases known as TDP-43 proteinopathies. Although TDP-43 pathology has been implicated in disease onset and progression, little is known about how TDP-43 becomes aggregated leading to progressive neurodegeneration. We seek to uncover the pathogenic mechanisms that promote TDP-43 aggregation, which will provide insights for future therapies against these debilitating diseases.
Post-translational modifications have been implicated in the progression of neurodegenerative diseases. We have previously demonstrated that acetylation of the tau protein promotes tangle formation in Alzheimer’s disease and related tauopathies. During the K99 mentoring phase of this proposal, we have demonstrated that TDP-43 acetylation similarly occurs in ALS post-mortem spinal cord characterized by TDP-43 pathology, highlighting a new TDP-43 modification that is potentially linked to ALS and related TDP-43 proteinopathies. The central hypothesis of this proposal is to determine whether acetylation impairs TDP-43 function and initiates pathological aggregation as a disease mechanism. The independent R00 phase of this proposal will now provide mechanistic insight as to whether acetylated TDP-43 induces pathological hallmarks, toxicity, and a degenerative phenotype that recapitulates human TDP-43 proteinopathies. Using in vitro and cell-based approaches, we will investigate the biological significance of acetylation in altering TDP-43 binding to target genes and RNAs, thus promoting a loss of function phenotype. Finally, we will examine whether hyper-acetylated TDP-43 at specific lysine residues is sufficient, on its own, to initiate aggregation and promote neuronal cell death in vivo. These innovative studies will bring acetylation to the research forefront as a critical modification linked to the onset/progression of ALS and possibly other related TDP-43 proteinopathies.
Effective start/end date6/15/145/31/17


  • NIH National Institute of Neurological Disorders and Stroke (NINDS)


Amyotrophic Lateral Sclerosis
DNA-Binding Proteins
Frontotemporal Dementia
Spinal Cord
Frontotemporal Lobar Degeneration
Nuclear RNA
tau Proteins
Motor Neuron Disease
RNA-Binding Proteins
Post Translational Protein Processing
Nuclear Proteins
Protein Binding
Neurodegenerative Diseases