Yakhine-Diop, SMS;
Niso-Santano, M;
Rodríguez-Arribas, M;
Gómez-Sánchez, R;
Martínez-Chacón, G;
Uribe-Carretero, E;
Navarro-García, JA;
... Fuentes, JM; + view all
(2019)
Impaired Mitophagy and Protein Acetylation Levels in Fibroblasts from Parkinson's Disease Patients.
Molecular Neurobiology
, 56
(4)
pp. 2466-2481.
10.1007/s12035-018-1206-6.
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Impaired mitophagy and protein acetylation levels in fibroblasts from_2018.pdf - Accepted Version Download (4MB) | Preview |
Abstract
Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. While most PD cases are idiopathic, the known genetic causes of PD are useful to understand common disease mechanisms. Recent data suggests that autophagy is regulated by protein acetylation mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities. The changes in histone acetylation reported to be involved in PD pathogenesis have prompted this investigation of protein acetylation and HAT and HDAC activities in both idiopathic PD and G2019S leucine-rich repeat kinase 2 (LRRK2) cell cultures. Fibroblasts from PD patients (with or without the G2019S LRRK2 mutation) and control subjects were used to assess the different phenotypes between idiopathic and genetic PD. G2019S LRRK2 mutation displays increased mitophagy due to the activation of class III HDACs whereas idiopathic PD exhibits downregulation of clearance of defective mitochondria. This reduction of mitophagy is accompanied by more reactive oxygen species (ROS). In parallel, the acetylation protein levels of idiopathic and genetic individuals are different due to an upregulation in class I and II HDACs. Despite this upregulation, the total HDAC activity is decreased in idiopathic PD and the total HAT activity does not significantly vary. Mitophagy upregulation is beneficial for reducing the ROS-induced harm in genetic PD. The defective mitophagy in idiopathic PD is inherent to the decrease in class III HDACs. Thus, there is an imbalance between total HATs and HDACs activities in idiopathic PD, which increases cell death. The inhibition of HATs in idiopathic PD cells displays a cytoprotective effect.
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