The paradigm of protein acetylation in Parkinson's disease

Sokhna M.S. Yakhine-Diop; Guadalupe Martínez-Chacón; Elisabet Uribe-Carretero; Mireia Niso-Santano; Rosa A. González-Polo; José M. Fuentes

doi:10.4103/1673-5374.250575

摘要：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 (Yakhine-Diop et al., 2018b). Te 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 fnally 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 (Song et al., 2011) and rotenone (Feng et al., 2015) reduce HDAC activity, dieldrin (Song et al., 2010) enhances HAT activity. However in vivo, paraquat-induced upregulation of α-synuclein triggers histone hypoacetylation. Terefore, in PD models, proteins are hypoacetylated or hyperacetylated in response to a stimulus. All these controversies become a paradigm given that a HDAC inhibitor (Collins et al., 2015) as well as a HAT inhibitor can be cytoprotective (Yakhine-Diop et al., 2018a). 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 fbroblasts 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 di?erence between idiopathic (WT LRRK2) PD (IPD) and genetic (G2019S LRRK2) PD (GPD) under basal conditions. Tose changes were more evident with higher molecular weight (MW) proteins (Figure 1) displaying a hypoacetylation in IPD and a hyperacetylation in GPD cells (Yakhine-Diop et al., 2018a). With peptides subjected to LC-MS, we also observed that hypoacetylated peptides were more abundant in IPD cells than in GPD (Yakhine-Diop et al., 2018b).