Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43.

Garcia Morato J, Hans F, von Zweydorf F, Feederle R, Elsässer SJ, Skodras AA, Gloeckner CJ, Buratti E, Neumann M, Kahle PJ

Nat Commun 13 (1) 1223 [2022-03-09; online 2022-03-09]

Trans-activation response DNA-binding protein of 43 kDa (TDP-43) regulates RNA processing and forms neuropathological aggregates in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Investigating TDP-43 post-translational modifications, we discovered that K84 acetylation reduced nuclear import whereas K136 acetylation impaired RNA binding and splicing capabilities of TDP-43. Such failure of RNA interaction triggered TDP-43 phase separation mediated by the C-terminal low complexity domain, leading to the formation of insoluble aggregates with pathologically phosphorylated and ubiquitinated TDP-43. Introduction of acetyl-lysine at the identified sites via amber suppression confirmed the results from site-directed mutagenesis. K84-acetylated TDP-43 showed cytoplasmic mislocalization, and the aggregation propensity of K136-acetylated TDP-43 was confirmed. We generated antibodies selective for TDP-43 acetylated at these lysines, and found that sirtuin-1 can potently deacetylate K136-acetylated TDP-43 and reduce its aggregation propensity. Thus, distinct lysine acetylations modulate nuclear import, RNA binding and phase separation of TDP-43, suggesting regulatory mechanisms for TDP-43 pathogenesis.

SciLifeLab Fellow

Simon Elsässer

PubMed 35264561

DOI 10.1038/s41467-022-28822-7

Crossref 10.1038/s41467-022-28822-7

pmc: PMC8907366
pii: 10.1038/s41467-022-28822-7

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