Abstract
Mutations in the FUS gene cause amyotrophic lateral sclerosis (ALS-FUS). However, the exact pathogenic mechanism of mutant fused in sarcoma (FUS) protein is not completely understood. FUS is an RNA binding protein (RBP) localized predominantly in the nucleus, but ALS-linked FUS mutations can affect its nuclear localization signal impairing its import into the nucleus. This mislocalization to the cytoplasm facilitates FUS aggregation in cytoplasmic inclusions. Therapies targeting post translational modifications are rising as new treatments for ALS, in particular acetylation which could have a role in the dynamics of RBPs. Research using histone deacetylase (HDAC) inhibitors in FUS-ALS models showed that HDACs can influence cytoplasmic FUS localization. Inhibition of HDACs could promote acetylation of the FUS RNA binding domain (RRM) and altering its RNA interactions resulting in FUS maintenance in the nucleus. In addition, acetylation of FUS RRMs might also favor or disfavor its incorporation into pathological inclusions. In this review, we summarize and discuss the evidence for the potential role of HDACs in the context of FUS-ALS and we propose a new hypothesis based on this overview.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease (Renton et al, 2014)
Based on the results obtained using histone deacetylase (HDAC) inhibition in fused in sarcoma (FUS)-ALS (Arenas et al, 2020; Kuta et al, 2020), we propose a molecular mechanism that could link the different HDACs to FUS mislocalization and FUS-derived toxicity (Figures 3, 4)
Point mutations in the FUS RNA recognition motif (RRM) (K315/K316 residues) effectively decrease FUS binding to RNA (Liu et al, 2013), so we propose that acetylation of these residues could reduce FUS binding to RNA and thereby FUS mislocalization
Summary
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease (Renton et al, 2014). It is characterized by the selective degeneration of motor neurons in the motor cortex, brainstem and spinal cord. TDP-43 is the most common pathological protein as it accounts for almost 97% of ALS cases (Neumann et al, 2006; Ling et al, 2013). ALS-linked FUS and TARDBP mutations lead to a shift in this equilibrium resulting in the mislocalization of FUS and TDP-43 into the cytoplasm. We will give an overview of the data related to the role of acetylation of FUS, why it is important, and we will discuss the therapeutic potential of HDAC inhibition
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