Lukianenko, Nataliia Kang, Dong Min Bekci, Aybuke Kim, Yun Kyung Lim, Sungsu 2025-07-29T02:00:06Z 2025-07-29T02:00:06Z 2025-07-28 2025-10 0022-2836 https://pubs.kist.re.kr/handle/201004/152853 TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), are characterized by aberrant cytoplasmic mislocalization and aggregation of TDP-43. Here, we established a live-cell TDP43-BiFC model to visualize TDP-43 oligomerization in real time and screened diverse cellular stressors. Histone deacetylase (HDAC) inhibition emerged as the most potent trigger of TDP-43 oligomerization. In particular, selective inhibition of the shuttling HDAC4/5 with LMK-235 induced an early and robust formation of cytoplasmic TDP-43 oligomers, comparable to or even exceeding the effect of the pan-HDAC inhibitor apicidin. In contrast, nuclear-restricted HDAC1/3 inhibition by MS-275 prolonged TDP-43 retention in the nucleus with minimal cytoplasmic mislocalization or oligomerization, underscoring distinct roles for nuclear versus nucleocytoplasmic HDACs. Inhibition of cytoplasmic HDAC6 (tubastatin A) had no significant effect. Notably, both shuttling and pan-HDAC inhibition increased TDP-43 acetylation and promoted the accumulation of stable, disulfide-linked TDP-43 oligomers. These findings identify lysine acetylation as a key regulator of disulfide bond-dependent TDP-43 oligomerization and suggest that targeting nucleocytoplasmic HDACs could be a novel therapeutic strategy in TDP-43 proteinopathies. English Academic Press Nucleocytoplasmic HDAC Inhibition Drives Acetylation-dependent TDP-43 Mislocalization and Disulfide-linked Oligomerization Article 10.1016/j.jmb.2025.169318 1 Journal of Molecular Biology, v.437, no.19 Journal of Molecular Biology 437 19 Y scie scopus 001529590900001 2-s2.0-105009798397 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article DNA-BINDING PROTEIN NUCLEAR RNA