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

Jorge Garcia Morato, Friederike Hans, Felix Zweydorf, Regina Feederle, Simon J. Elsässer, Angelos A. Skodras, Christian Johannes Gloeckner, Emanuele Buratti, Manuela Neumann and Philipp J. Kahle ()
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Jorge Garcia Morato: Hertie Institute for Clinical Brain Research, University of Tübingen
Friederike Hans: Hertie Institute for Clinical Brain Research, University of Tübingen
Felix Zweydorf: German Center for Neurodegenerative Diseases (DZNE)
Regina Feederle: Institute for Diabetes and Obesity, Monoclonal Antibody Core Facility, Helmholtz Munich
Simon J. Elsässer: Karolinska Institutet
Angelos A. Skodras: University of Tübingen
Christian Johannes Gloeckner: German Center for Neurodegenerative Diseases (DZNE)
Emanuele Buratti: Molecular Pathology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB)
Manuela Neumann: German Center for Neurodegenerative Diseases (DZNE)
Philipp J. Kahle: Hertie Institute for Clinical Brain Research, University of Tübingen

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28822-7

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