An acetylation switch controls TDP-43 function and aggregation propensity

Topic: Brain proteins, microglia and lab models

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.

Key findings

• 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.

Why it matters

In laboratory and cell experiments, acetylation of TDP-43 reduced its RNA binding and promoted insoluble, hyper-phosphorylated clumps resembling those seen in ALS and FTLD-TDP, and acetylated TDP-43 lesions were found in ALS patient spinal cord. The authors suggest modulating acetylation as a possible strategy, but no treatment was tested in patients.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/ncomms6845
• PubMed: 25556531
• Original source →
• Free full text: Nature Communications →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{cohen2015-25556531,
  author  = {Cohen, T. J. and Hwang, A. W. and Restrepo, C. R. and Yuan, C. X. and Trojanowski, J. Q. and Lee, V. M.},
  title   = {{An acetylation switch controls TDP-43 function and aggregation propensity}},
  journal = {Nature communications},
  year    = {2015},
  doi     = {10.1038/ncomms6845},
  pmid    = {25556531},
  url     = {https://doi.org/10.1038/ncomms6845}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 18.

• Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations Annals of neurology · 2007-05-01 · usefulness score 63/100 · Brain tissue and pathology
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Characterizing the RNA targets and position-dependent splicing regulation by TDP-43 Nature neuroscience · 2011-02-27 · usefulness score 61/100 · Lewy body dementia
• TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration Human molecular genetics · 2010-04-15 · usefulness score 56/100 · Lewy body dementia
• Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Annals of neurology · 2008-07-01 · usefulness score 54/100 · Lewy body dementia
• Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis The Journal of neuroscience : the official journal of the Society for Neuroscience · 2010-01-01 · usefulness score 54/100 · Lewy body dementia
• Acetylation of tau inhibits its degradation and contributes to tauopathy Neuron · 2010-09-01 · usefulness score 54/100 · Lewy body dementia
• Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation The Journal of biological chemistry · 2008-02-27 · usefulness score 53/100 · Lewy body dementia
• TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity The Journal of biological chemistry · 2009-05-22 · usefulness score 53/100 · Lewy body dementia
• TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration Proceedings of the National Academy of Sciences of the United States of America · 2009-10-15 · usefulness score 52/100 · Lewy body dementia
• TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration Proceedings of the National Academy of Sciences of the United States of America · 2010-02-03 · usefulness score 52/100 · Lewy body dementia
• Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice The Journal of clinical investigation · 2011-01-04 · usefulness score 52/100 · Lewy body dementia

Later studies that cite this one

13 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• An acetylated Tau-174 CSF biomarker discriminates between TDP-43 and tau pathology in patients with frontotemporal lobar degeneration Nature Medicine · 2026-04-15 · usefulness score 63/100 · Brain tissue and pathology
• SUMO2/3 conjugation of TDP-43 protects against aggregation Science Advances · 2025-02-21 · usefulness score 52/100 · Brain tissue and pathology
• Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis Frontiers in molecular neuroscience · 2019-02-14 · usefulness score 50/100 · Lewy body dementia
• FUS and TDP-43 Phases in Health and Disease Trends in biochemical sciences · 2021-01-11 · usefulness score 49/100 · Lewy body dementia
• PARylation regulates stress granule dynamics, phase separation, and neurotoxicity of disease-related RNA-binding proteins Cell research · 2019-02-06 · usefulness score 49/100 · Brain tissue and pathology
• Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins Journal of neurochemistry · 2016-06-15 · usefulness score 49/100 · Lewy body dementia
• Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration Molecular Neurodegeneration · 2025-05-08 · usefulness score 48/100 · Brain tissue and pathology
• TDP-43 seeding activity in the olfactory mucosa of patients with amyotrophic lateral sclerosis Molecular Neurodegeneration · 2025-04-26 · usefulness score 46/100 · Brain tissue and pathology

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• Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity Proceedings of the National Academy of Sciences of the United States of America · 2009-04-21 · usefulness score 55/100
• Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation Nature communications · 2017-06-29 · usefulness score 55/100
• Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice The Journal of neuroscience : the official journal of the Society for Neuroscience · 2010-08-01 · usefulness score 53/100
• ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43 Proceedings of the National Academy of Sciences of the United States of America · 2013-02-04 · usefulness score 53/100
• The role of liquid-liquid phase separation in aggregation of the TDP-43 low-complexity domain The Journal of biological chemistry · 2019-02-27 · usefulness score 50/100
• Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo Human molecular genetics · 2009-12-03 · usefulness score 50/100

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