Fig. 7.
HDAC inhibitors and arimoclomol preserve nuclear localization of TDP-43. Cultures containing motor neurons expressing TDP-43G348C or wild-type TDP-43 were treated with vehicle (DMSO), 4 µM arimoclomol, or HDAC inhibitor (4 µM SAHA, 1 µM RGFP963, 4 µM RGFP109, or 1 µM Tubastatin A) alone or in combination with arimoclomol. (a) After 3 days, cultures were immunolabeled with rabbit anti-TDP-43 and TDP-43 localization was categorized as: cytoplasmic only, both nuclear and cytoplasmic, and nuclear only. (b) SAHA, (c) RGFP109, or (d) RGFP963 significantly preserved nuclear TDP-43 in motor neurons expressing TDP-43G348C. Arimoclomol treatment also significantly maintained nuclear TDP-43. (e) No effect of the HDAC6 inhibitor Tubastatin A. (f) Neither overexpression of wild-type TDP-43 nor treatment of these neurons with drugs affected TDP-43 distribution. Data are presented as mean ± SD. Each data point on the graph represents the mean % of neurons in each of 6–9 cultures (12–45 neurons/culture). Statistical significance was evaluated by one-way ANOVA followed by Dunnett's multiple comparison test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Scale bar = 20 µm. Abbreviations used: HDAC, histone deacetylase; SAHA, suberoylanilide hydroxamic acid; SD, standard deviation; TDP-43, TAR DNA binding protein 43 kDa. 43 kDa; DMSO dimethyl sulfoxide.