Parkinson's Disease Associated with GBA Gene Mutations: Molecular Aspects and Potential Treatment Approaches.

Parkinson's disease (PD) is a multifactorial neurodegenerative disease. To date, genome-wide association studies have identified more than 70 loci associated with the risk of PD. Variants in the GBA gene encoding glucocerebrosidase are quite often found in PD patients in all populations across the world, which justifies intensive investigation of this gene. A number of biochemical features have been identified in patients with GBA-associated Parkinson's disease (GBA-PD). In particular, these include decreased activity of glucocerebrosidase and accumulation of the glucosylceramide substrate. These features were the basis for putting forward a hypothesis about treatment of GBA-PD using new strategies aimed at restoring glucocerebrosidase activity and reducing the substrate concentration. This paper discusses the molecular and genetic mechanisms of GBA-PD pathogenesis and potential approaches to the treatment of this form of the disease.

Ambroxol increases glucocerebrosidase (GCase) activity and restores GCase translocation in primary patient-derived macrophages in Gaucher disease and Parkinsonism.

Mutations in the glucocerebrosidase gene (GBA) encoding the lysosomal enzyme glucocerebrosidase (GCase) cause Gaucher disease (GD) and are the most commonly known genetic risk factor for Parkinson disease (PD). Ambroxol is one of the most effective pharmacological chaperones of GCase. Fourteen GD patients, six PD patients with mutations in the GBA gene (GBA-PD), and thirty controls were enrolled. GCase activity and hexosylsphingosine (HexSph) concentration were measured in dried blood and macrophage spots using liquid chromatography coupled with tandem mass spectrometry. The effect of ambroxol on GCase translocation to lysosomes was assessed using confocal microscopy. The results showed that ambroxol treatment significantly increased GCase activity in cultured macrophages derived from patient blood monocytic cell (PBMC) of GD (by 3.3-fold) and GBA-PD patients (by 3.5-fold) compared to untreated cells (p < 0.0001 and p < 0.0001, respectively) four days after cultivation. Ambroxol treatment significantly reduced HexSph concentration in GD (by 2.1-fold) and GBA-PD patients (by 1.6-fold) (p < 0.0001 and p < 0.0001, respectively). GD macrophage treatment resulted in increased GCase level and increased enzyme colocalization with the lysosomal marker LAMP2. The possible binding modes of ambroxol to mutant GCase carrying N370S amino acid substitution at pH 4.7 were examined using molecular docking and molecular dynamics simulations. The ambroxol position characterized by minimal binding free energy was observed in close vicinity to the residue, at position 370. Taken together, these data showed that PBMC-derived macrophages could be used for assessing ambroxol therapy response for GD patients and also for GBA-PD patients.

Genetics variants and expression of the SCARB2 gene in the pathogenesis of Parkinson's disease in Russia.

Lysosomal integral membrane protein-2 (LIMP-2), encoded by the SCARB2 gene, is the specific lysosomal receptor for glucocerebrosidase enzyme. Association between rs6812193 and rs68250047 of SCARB2 with PD has been shown in genetic studies, including large genome-wide association studies. The aim of the current study was to determine whether rs6812193 and rs8475 are associated with PD in Russia. rs6812193 and rs8475 were genotyped in a total of 604 PD patients (65 PD patients with positive (fPD) and 539 PD patients with negative family history (sPD)) and 413 controls and also in 17 patients with PD associated with GBA mutations (PD-GBA) and 18 asymptomatic GBA mutation carriers (GBA-Carriers). SCARB2 expression was measured by real-time PCR in CD45+ blood cells in part of individuals in the studied groups. No linkage disequilibrium was shown between rs6812193 and rs8475 in Russian population. Increased PD risk for TT variant of rs8475 (OR = 2.02; p < 0.001) was found in sPD patients but not in fPD. rs6812193 and rs8475 were not associated with age at onset (AAO) of PD. SCARB2 expression level was decreased in GBA-PD patients and GBA-Carriers compared to PD patients (padjusted = 0.02, padjusted = 0.003, respectively) and GBA-Carriers compared to controls (padjusted = 0.013) with no significant difference in PD patients and controls. SCARB2 expression was not modified with rs6812193 and rs8475. In conclusion, rs8475 was associated with PD status. rs6812193 and rs8475 are not genetic modifier of AAO of PD and do not influence on SCARB2 mRNA level in CD45+ blood cells in studied groups. SCARB2 expression could be modified with GBA mutations and is independent of PD status.

[The clinical features of Parkinson's disease in patients with mutations and polymorphic variants of GBA gene]. / Klinicheskie osobennosti bolezni Parkinsona u patsientov s mutatsiiami i polimorfnymi variantami gena GBA.

BACKGROUND: Mutations in the glucocerebrosidase gene (GBA) increase the risk of Parkinson's disease (PD) by 6-10 times in all populations and are associated with the early-onset of PD, development of cognitive impairment and presence of psychotic disorders. At the same time, polymorphic variants associated with the twofold increase in the risk of PD were also described in the GBA gene. AIM: To estimate the clinical features of PD in patients with mutations and polymorphic variants of the GBA gene. MATERIAL AND METHODS: Evaluation of motor, cognitive, emotional, psychotic and autonomic dysfunctions in patients with mutations (N370S, L444P) and polymorphic variants (E326K, T369M) in the GBA gene was performed using clinical scales. RESULTS: Patients with mutations (mGBA-PD), and with polymorphic variants (pGBA-PD) in the GBA gene were compared with the group of patients with sporadic PD (sPD). Compared to sPD, affective disorders (depression and anxiety) were more expressed in the mGBA-PD group (p=0.001) and the general GBA-PD group (p=0.001) assessed with Sheehan anxiety rating scale, in the pGBA-PD group (p=0.012) and the general GBA-PD group (p=0.05) assessed with the NPI, in the mGBA-PD (p=0.003), pGBA-PD (p=0.022), and general GBA-PD groups (p=0.001) assessed with the Hospital Anxiety and Depression scale (HADS 'A'), and in the pGBA-PD group (p=0.005) assessed with the HADS 'D'. Non-motor symptoms assessed with the PD-NMS were more expressed in the pGBA-PD patients (p=0.007) and in the total group with GBA-PD (p=0,014) compared to sPD. Cognitive impairment measured with MMSE was more marked in mGBA-PD patients (p=0.022). Differences in motor and non-motor clinical symptoms between pGBA-PD and mGBA-PD groups were not found. CONCLUSION: Thus, clinical features of non-motor symptoms were described both in carriers of GBA mutations and polymorphisms. Identification of the specific clinical phenotype of PD in carriers of GBA polymorphic variants is important due to their relatively high prevalence in PD patients.

ITLN1, PPARg AND TNFa GENE EXPRESSION IN VISCERAL ADIPOSE TISSUE.

The adipose tissue is considered today as an endocrine organ in which tissue-specific regulation of gene expression plays a key role in the processes of development of obesity and comorbidities, such as diabetes and cardiovascular disease. The present study is focused on ITLN1, PPARã and TNFá gene expression in intra-abdominal adipose tissue and its effect on the serum levels of omentin 1 and TNFa in individuals with different body mass. It has been shown that serum TNFa level is significantly higher in the subgroup of patients with overweight and obesity (BMI ≥ 25 kg/m2) as compared to individuals with normal body weight (BMI < 25 kg/m2)( p < 0.03). We have demonstrated that the expression level of the PPARã gene is positively correlated with the ITLN1 gene expression level in the intra-abdominal adipose tissue (r = 0.516, p = 0.020). Serum level of omentin 1 positively correlates with PPARã mRNA and protein levels in intra-abdominal adipose tissue (r = 0.550, p < 0.05 and r = 0.581, p < 0.03, respectively). For the subgroup of patients with overweight and obesity, we have shown negative correlation of the level of TNFá mRNA with PPARã and ITLN1 mRNA levels was shown (r = ­0.549, p < 0.05 and r = ­0.475, p < 0.05, respectively). This study is the first to show a correlation relationship between PPARã gene expression level in the intra-abdominal adipose tissue and the expression and secretion levels of omentin 1.