Abstract:

Acetylation is a post-translational modification that is regulated by two antagonistic enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs transfer the acetyl group from acetyl-CoA to lysine residues of proteins while HDACs remove it. The impairment of HAT or HDAC activity elicits changes in the protein acetylation status which disturb several cellular processes, among others, gene expression, autophagy etc., leading finally to cell death. Both enzymes are associated with Parkinson’s disease (PD) pathogenesis. In dopaminergic cells, neurotoxins provoke apoptotic cell death by increasing histone acetylation levels. While paraquat and rotenone reduce HDAC activity, dieldrin enhances HAT activity. However in vivo, paraquat-induced upregulation of α-synuclein triggers histone hypoacetylation. Therefore, in PD models, proteins are hypoacetylated or hyperacetylated in response to a stimulus. All these controversies become a paradigm given that a HDAC inhibitor as well as a HAT inhibitor can be cytoprotective. Most of the studies that link acetylation to PD generally focus on the level of histone acetylation. Recently, a comparative study has been performed in two groups of fibroblasts from PD patients with or without the G2019S leucine-rich repeat kinase 2 (LRRK2) mutation. This is the first time that, by western-blotting, a smear of acetylated proteins as a whole reveals the difference between idiopathic (WT LRRK2) PD (IPD) and genetic (G2019S LRRK2) PD (GPD) under basal conditions. Those changes were more evident with higher molecular weight (MW) proteins displaying a hypoacetylation in IPD and a hyperacetylation in GPD cells. With peptides subjected to LC-MS, we also observed that hypoacetylated peptides were more abundant in IPD cells than in GPD.