LRRK2 exonic variants are associated with lysosomal hydrolase activities and lysosphingolipid alterations in Parkinson's disease.

Last data demonstrated that exonic variants of LRRK2 (p.G2019S, p.M1646T) may affect the catalytic activity of lysosomal enzyme glucocerebrosidase (GCase) probably through the phosphorylation of Rab10 protein. We aimed to evaluate an association of LRRK2 exonic variants previously associated with alteration of phosphorylation levels for Rab10Thr73 with PD risk in Russian population and analyze an impact of p.G2019S mutation and selected LRRK2 variants on lysosomal hydrolase activities. LRRK2 variants were determined by full sequencing of LRRK2 in 508 PD patients and 470 controls from Russian population. Activity of lysosomal enzymes (glucocerebrosidase (GCase), alpha-galactosidase A (GLA), acid sphingomyelinase (ASMase) and concentrations of their corresponded substrates (hexosylsphingosine (HexSph), globotriaosylsphingosine (LysoGb3), lysosphingomyelin (LysoSM), respectively) were estimated in 211 PD patients and 179 controls by liquid chromatography with tandem mass spectrometry (LC-MS-MS) in dry blood spots. p.M1646T and p.N2081D were associated with PD (OR = 2.33, CI 95%: 1.1215 to 4.8253, p = 0.023; OR = 1.89, 95%CI: 1.0727 to 3.3313, p = 0.028, respectively) in Russian population. An increased LysoGb3 concentration was found in p.G2019S and p.N2081D LRRK2 carriers among PD patients compared to both PD patients and controls (p.G2019S: p = 0.00086, p = 0.0004, respectively; p.N2081D: p = 0.012, p = 0.0076, respectively). A decreased ASMase activity in p.G2019S LRRK2 carriers among PD patients (p = 0.014) was demonstrated as well. Our study supported possible involvement of LRRK2 dysfunction in an alteration of sphingolipid metabolism in PD.

[The effect of antipsychotic drug on monoamine receptors in peripheral blood mononuclear cells: affinity linked mechanism]. / Vliianie antipsikhoticheskikh preparatov na retseptory monoaminov mononuklearnykh kletok perifericheskoi krovi: affinitet-stseplennyi mekhanizm.

Schizophrenia is one of the most serious and common mental disorders, which is characterized by high levels of pathogenic heterogeneity as well as neuroimmune abnormalities, which require treatment with antipsychotic drugs. Monoamines are one of the key neurotransmitters which play an important role in neuroimmune interactions of the human organism. We suggest that the quantity of the monoamine receptors on mononuclear cells of the peripheral blood (PBMCs) can be associated with the cytokine profile of patients. With this quantity being a key component of the mental status correction mechanism in antipsychotic therapy. In this study we measured cytokine levels (IL-6, IL-1b and TGF-b) in blood serum, the protein expression status of the serotonin receptor 5HTR2A and the dopamine receptors D1 (DRD1), DRD2, DRD3 in PBMCs of drug-naive, first episode schizophrenia patients before and after the treatment with olanzapine and haloperidol. This study has shown for the first time that the antipsychotic therapy leads to a decrease in protein levels of monoamine receptors in PBMCs associated with the affinity of the drug used. Blood cytokine levels were significantly higher in serum from studied patients as compared with the reference values. The antipsychotic-linked change of the TGF-b production caused by the therapy is probably associated with the reduction of various monoamine receptors. The relationship between the psychopathological status and the protein level of 5THR2A suggests that the amount of 5HTR2A may serve as a potential biomarker for the personalized appointment of the antipsychotic therapy.

Potential diagnostic markers of olanzapine efficiency for acute psychosis: a focus on peripheral biogenic amines.

BACKGROUND: Biomarkers are now widely used in many fields of medicine, and the identification of biomarkers that predict antipsychotic efficacy and adverse reactions is a growing area of psychiatric research. Monoamine molecules of the peripheral bloodstream are possible prospective biomarkers based on a growing body of evidence indicating that they may reflect specific changes in neurotransmitters in the brain. The aim of this study was to detect peripheral biogenic amine indicators of patients with acute psychosis and to test the correlations between the biological measures studied and the psychopathological status of the patients. METHODS: This research included 60 patients with acute psychosis treated with olanzapine (n = 30) or haloperidol (n = 30). Here, we measured biogenic amine indicators, including mRNA levels of dopamine receptor D4 (DRD4) and the serotonin 2A receptor (5HTR2A), in peripheral blood mononuclear cells (PBMCs) using quantitative real-time polymerase chain reaction and serum dopamine concentrations by enzyme linked immunosorbent assay (ELISA). Psychopathological status was evaluated using psychometric scales. The assessments were conducted prior to and after 14 and 28 days of treatment. RESULTS: The administration of haloperidol, but not olanzapine, up-regulated 5HTR2A mRNA in a linear manner, albeit without statistical significance (p = 0.052). Both drugs had non-significant effects on DRD4 mRNA levels. Nevertheless, a positive correlation was found between DRD4 and 5HTR2A mRNA levels over a longitudinal trajectory, suggesting co-expression of the two genes. A significant positive correlation was observed between 5HTR2A mRNA levels and total Positive and Negative Syndrome Scale (PANSS) scores in both groups of patients before treatment. A significant correlation between baseline 5HTR2A mRNA levels and PANSS scores on days 14 and 28 of treatment remained for patients treated with olanzapine only. Moreover, a significant positive correlation was observed between blood serum dopamine levels and scores on extrapyramidal symptom scales in the olanzapine group. CONCLUSIONS: The DRD4 and 5HTR2A genes are co-expressed in PBMCs during antipsychotic administration. Despite a correlation between the studied biogenic amine indicators and the psychopathological status of patients, reliable biomarkers of treatment response could not be determined.

The Key Proteins of Dopaminergic Neurotransmission of Human Peripheral Blood Lymphocytes: Changed mRNA Level in Alcohol Dependence Syndrome.

The expression of dopamine receptor (DRD), Nurr1 transcription factor (NR4A2), and α-sinucleine (SNCA) genes in peripheral blood lymphocytes is evaluated. The results indicate that alcohol dependence is associated with high expression of SNCA and DRD4 (signifi cantly higher than in the control group) and is not associated with changes in the work of NR4A2 and DRD3 genes. The levels of DRD3 and DRD4 mRNA form a positive linear correlation (p≤0.05). The expression of SNCA and DRD4 genes can serve as an important peripheral marker of alcohol dependence development, which is essential for antipsychotic therapy.

[Dopamine neurotransmission of peripheral blood lymphocytes is a potential biomarker of psychiatric and neurological disorders].

Current literature on a role of dopamine in the development of mental and neurological disorders suggests that the discovery of endogenous dopamine in peripheral blood lymphocytes gave rise to a new line of research. Dopamine receptors are not only found on cells of the innate immune response (nonspecific), but also on cells of adaptive immune response (specific): T and B lymphocytes. These facts bring a new evidence of interrelationships between the peripheral immune system, neuroinflammation and neurodegeneration and suggest new ways for investigation of the pathogenesis of different mental and neurological disorders, in particular Parkinson's disease, Alzheimer's disease and schizophrenia. There is strong evidence that ligands of dopamine receptors can change the expression of coding genes both in central neurons and in peripheral cells. Thus, peripheral blood lymphocytes may prove a cellular tool to identify dopamine transmission disturbances in neuropsychiatric diseases, as well as to monitor the effects of pharmacological treatment.