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.

Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration

“…Yoo et al found that it decreases the level of motor neuron cell death and ameliorates muscle atrophy and neuromuscular junction denervation in an SOD1 ALS mouse model [ 246 ]. Very recently, Bennett et al report that TSA suppresses FUS-associated toxicity and relieves growth suppression by controlling histone acetylation on specific modification sites using a FUS ALS/FTD yeast model [ 247 ], which further supports the clinical potential of TSA in the treatment of ALS. In another study, TSA treatment induces the expression of SMN2 and improves survival and motor pathology in SMA mice [ 248 ].…”

Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases

“…Treatment with the HDAC inhibitor MS-275 and theAMPK/sirtuin 1 activator resveratrol normalized RelA acetylation in sOD1(G93A) mice, delayed disease onset, enhanced motor function, prolonged lifespan, and rescued lumbar motor neurons affected in sOD1(693 A) mice [ 111 ]. Trichostatin A, a histone deacetylase inhibitor, alleviates growth inhibition and restores histone acetylation at specific sites in a FUS ALS/FTD yeast model, offering a new mechanistic basis for alternative therapeutic strategies in ALS/FTD and other neurodegenerative disorders [ 112 ]. Acetylation (neutralization) of multiple lysines by aspirin can increase the intrinsic net negative charge of the polypeptide and inhibit the amyloidogenesis of superoxide dismutase (SOD1) [ 113 ].…”

Saccharomyces cerevisiae as a research tool for RNA‐mediated human disease

“…Another study also showed that phosphorylation of FUS's PLD can inhibit solid‐phase aggregation while minimally altering liquid‐phase condensation (Owen et al, 2020). These data point to post‐translational modifications such as phosphorylation and histone acetylation as potential treatment targets (Bennett et al, 2019; Bennett et al, 2021; Chen et al, 2018).…”