The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index.
An acetylation switch controls TDP-43 function and aggregation propensity
Open accessAbstract
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. The nuclear protein TDP-43 is implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Here, Cohen et al. discover lysine acetylation as a modification that regulates TDP-43 function, providing a mechanism that could be implicated in the pathogenesis of TDP-43 proteinopathies.
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Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
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Self-citationLysine acetylation targets protein complexes and co-regulates major cellular functions
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Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43
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HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS.
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Characterizing the RNA targets and position-dependent splicing regulation by TDP-43
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Stages of pTDP‐43 pathology in amyotrophic lateral sclerosis
Brettschneider, J., Del Tredici, K., Toledo, J. B., Robinson, J. L., Irwin, D. J., Grossman, M., Suh, E., Van Deerlin, V. M., Wood, E. M., Baek, Y., et al. (2013) · Annals of Neurology · doi:10.1002/ana.23937 · Cited by 1,065
Self-citationTDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration
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Self-citationAcetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy
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Functions and mechanisms of non-histone protein acetylation
Narita, T., Weinert, B. T., & Choudhary, C. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0081-3 · Cited by 1,232
Modulation of cellular processes by histone and non-histone protein acetylation
Shvedunova, M., & Akhtar, A. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00441-y · Cited by 936
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis
Prasad, A., Bharathi, V., Sivalingam, V., Girdhar, A., & Patel, B. K. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00025 · Cited by 774
ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?
Mejzini, R., Flynn, L. L., Pitout, I. L., Fletcher, S., Wilton, S. D., & Akkari, P. A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01310 · Cited by 755
The role of mitochondria in amyotrophic lateral sclerosis
Smith, E. F., Shaw, P. J., & De Vos, K. J. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2017.06.052 · Cited by 559
Metadata
- Authors
- Cohen, T. J., Hwang, A. W., Restrepo, C. R., Yuan, C.-X., Trojanowski, J. Q., & Lee, V. M. Y.
- Venue
- Nature Communications
- Published
- 2015-01-05
- Volume
- 6
- Issue
- 1
- Pages
- 5845-5845
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2082602037
- Cited by
- 362
- References
- 68
- FWCI
- 10.53
- Type
- journal article
- Language
- en
- Open access
- gold
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- Cohen, T. J., Hwang, A. W., Restrepo, C. R., Yuan, C.-X., Trojanowski, J. Q., & Lee, V. M. Y. (2015). An acetylation switch controls TDP-43 function and aggregation propensity. Nature Communications. https://doi.org/10.1038/ncomms6845
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