Trichostatin A Relieves Growth Suppression and Restores Histone Acetylation at Specific Sites in a FUS ALS/FTD Yeast Model

Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that often occurs concurrently with frontotemporal dementia (FTD), another disorder involving progressive neuronal loss. ALS and FTD form a neurodegenerative continuum and share pathological and genetic features. Mutations in a multitude of genes have been linked to ALS/FTD, including FUS. The FUS protein aggregates and forms inclusions within affected neurons. However, the precise mechanisms connecting protein aggregation to neurotoxicity remain under intense investigation. Recent evidence points to the contribution of epigenetics to ALS/FTD. A main epigenetic mechanism involves the post-translational modification (PTM) of histone proteins. We have previously characterized the histone PTM landscape in a FUS ALS/FTD yeast model, finding a decreased level of acetylation on lysine residues 14 and 56 of histone H3. Here, we describe the first report of amelioration of disease phenotypes by controlling histone acetylation on specific modification sites. We show that inhibiting histone deacetylases, via treatment with trichostatin A, suppresses the toxicity associated with FUS overexpression in yeast by preserving the levels of H3K56ac and H3K14ac without affecting the expression or aggregation of FUS. Our data raise the novel hypothesis that the toxic effect of protein aggregation in neurodegeneration is related to its association with altered histone marks. Altogether, we demonstrate the ability to counter the repercussions of protein aggregation on cell survival by preventing specific histone modification changes. Our findings launch a novel mechanistic framework that will enable alternative therapeutic approaches for ALS/FTD and other neurodegenerative diseases.

Figure 1.. Trichostatin A relieves growth suppression in a FUS ALS/FTD yeast model.

Yeast expressing FUS or an empty vector were serially diluted 5-fold and spotted on glucose (off) or galactose (on) medium in the absence (untreated, DMSO) or presence of TSA at varying concentrations. Densitometric measurement of cell density compared to the untreated control is depicted. Box plot whiskers represent upper and lower quartiles. *** = p < 0.001, ** = p < 0.01. n = 4.

Figure 2.. Trichostatin A restores acetylation on Lysines 14 and 56 of Histone H3 in yeast FUS ALS/FTD models.

Representative Western blots displaying the levels of H3K14ac (A, n = 6) and H3K56ac (B, n = 6) are shown. Histograms compiling multiple biological replicates are shown. (C) Putative mechanism for TSA effects in FUS ALS/FTD yeast models. Error bars represent +SD. * = p < 0.05, ** = p < 0.01, *** = p < 0.001.