Effect of LRRK2 Inhibition on the Activity of Glucocerebrosidase in Patient-Specific Cells from Patients with Gaucher Disease.

Biallelic mutations in the gene encoding lysosomal enzyme glucocerebrosidase (GCase), lead to the development of the Gaucher disease (GD) and also represent a significant risk factor for the Parkinson's disease (PD). In most cases, mutations in the gene are located outside the region coding for the enzyme active site and cause a decrease in the GCase activity due to the reduction in the efficiency of transport of conformationally altered enzyme to the lysosomes. Drugs used to treat GD (enzyme replacement therapy) cannot cross the blood-brain barrier and, therefore, are not effective in the treatment of neuronal forms of GD or PD associated with mutations in the gene (GBA1-PD).

[Template Properties of 5-Methyl-2'-Deoxycytidine and 5-Hydroxymethyl-2'-Deoxycytidine in Reactions with Human Translesion and Reparative DNA Polymerases].

5-Methyl-2'-deoxycytidine (mC) and the product of its controlled oxidation, 5-hydroxymethyl-2'-cytidine (hmC), play a key role in the epigenetic regulation of gene expression, the cell differentiation, and the carcinogenesis. Due to spontaneious deamination, genomic CpG sites containing mC and hmC serve as mutagenesis hotspots. In addition, error-prone translesion and reparative DNA polymerases may serve as additional source of mutations in the lesion-containing regions with CpG sites.