Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease

Background

Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD), and are especially prevalent in the Ashkenazi Jewish (AJ) population. However, most studies on GBA in AJ genotype only seven selected Gaucher-associated pathogenic variants rather than sequencing the whole gene, which may leave carriers of PD-associated GBA variants undiscovered.

A new function for the serine protease HtrA2 in controlling radiation‐induced senescence in cancer cells

Radiation therapy can induce cellular senescence in cancer cells, leading to short‐term tumor growth arrest but increased long‐term recurrence. To better understand the molecular mechanisms involved, we developed a model of radiation‐induced senescence in cultured cancer cells. The irradiated cells exhibited a typical senescent phenotype, including upregulation of p53 and its main target, p21, followed by a sustained reduction in cellular proliferation, changes in cell size and cytoskeleton organization, and senescence‐associated beta‐galactosidase activity. Mass spectrometry‐based proteomic profiling of the senescent cells indicated downregulation of proteins involved in cell cycle progression and DNA repair, and upregulation of proteins associated with malignancy. A functional siRNA screen using a cell death‐related library identified mitochondrial serine protease HtrA2 as being necessary for sustained growth arrest of the senescent cells. In search of direct HtrA2 substrates following radiation, we determined that HtrA2 cleaves the intermediate filament protein vimentin, affecting its cytoplasmic organization. Ectopic expression of active cytosolic HtrA2 resulted in similar changes to vimentin filament assembly. Thus, HtrA2 is involved in the cytoskeletal reorganization that accompanies radiation‐induced senescence and the continuous maintenance of proliferation arrest.     

Decreasing battery life in subthalamic deep brain stimulation for Parkinson's disease with repeated replacements: Just a matter of energy delivered?

BackgroundPeople with Parkinson's disease (PD) treated with deep brain stimulation (DBS) with non-rechargeable implantable pulse generators (IPGs) require elective IPG replacement operations involving surgical and anesthesiologic risk. Life expectancy and the number of replacements per patient with DBS are increasing.ObjectiveTo determine whether IPG longevity is influenced by stimulation parameters alone or whether there is an independent effect of the number of battery replacements and IPG model.MethodsPD patients treated with bilateral subthalamic DBS were included if there was at least one IPG replacement due to battery end of life. Fifty-five patients had one or two IPG replacements and seven had three or four replacements, (80 Kinetra® and 23 Activa-PC®). We calculated longevity corrected for total electrical energy delivered (TEED) and tested for the effect of IPG model and number of previous battery replacements on this measure.ResultsTEED-corrected IPG longevity for the 1^st implanted IPG was 51.3 months for Kinetra® and 35.6 months for Activa-PC®, which dropped by 5.9 months and 2.8 months, respectively with each subsequent IPG replacement (p < 10^–6 for IPG model and p < 10^–3 for IPG number).ConclusionsActiva-PC® has shorter battery longevity than the older Kinetra®, battery longevity reduces with repeated IPG replacements and these findings are independent of TEED. Battery longevity should be considered both in clinical decisions and in the design of new DBS systems. Clinicians need accessible, reliable and user-friendly tools to provide online estimated battery consumption and end of life. Furthermore, this study supports the consideration of using rechargeable IPGs in PD.     

MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish–Ashkenazi descent

A functional single nucleotide polymorphism in the promoter of the MDM2 gene, SNP309 (T>G), was recently found to accelerate tumorigenesis in early onset cancer cases. The SNP309 G-allele, introduces an SP1 site in the MDM2 promoter, resulting in enhanced MDM2 expression and activity. Thus, the G-allele of MDM2 SNP309 may represent a cancer predisposing allele. In this report, we assessed the role of SNP309 as a modifier of mutant BRCA1/BRCA2 alleles in inherited breast and ovarian cancer cases among Ashkenazi–Jewish (AJ) women. We genotyped several subsets of AJ women: 138 healthy women, 140 affected BRCA1/2 mutation carriers, 120 asymptomatic BRCA1/2 mutation carriers and 187 sporadic breast cancer patients. The frequency of GG genotype of SNP309 was similar among the different groups. Interestingly, we found almost three times higher frequency of the GG genotype among BRCA1/2 carriers diagnosed with breast and/or ovarian cancer at or under the age of 51 years compared with carriers diagnosed with cancer above the age of 51 years (allele frequency, P = 0.019). The GG genotype was significantly associated with breast and ovarian cancer risk among BRCA1/2 carriers diagnosed before 51 years of age (OR, 3.93; 95% CI, 1.41–10.90, P = 0.009). No significant difference in frequency of the GG genotype was observed between early and late onset non-carrier cancer patients and no association with risk, OR, 1.30; 95% CI 0.69–2.47, P = 0.419). These data suggest that MDM2 SNP309 acts as a modifier of mutant BRCA1/2 mutant alleles in AJ and may accelerate breast and ovarian carcinogenesis in genetically predisposed individuals.     

Association of the dopamine receptor interacting protein gene, NEF3, with early response to antipsychotic medication

Genetic variation in antipsychotic drug targets could underlie variability among patients in the time required for antipsychotic effects to be elicited. In a clinical, pharmacogenetic study we focused on the dopamine receptor interacting protein (DRIP) gene family. DRIPs are pivotally involved in regulating dopamine receptor signal transduction. Consecutively hospitalized, acutely psychotic patients with DSM-IV schizophrenia (n=121) were included in the study if they received treatment with typical antipsychotic medication (TYP, n=72) or TYP plus risperidone (TYP-R, n=49) for at least 2 wk. Clinical state and adverse effects were rated at baseline and after 2 wk. Patients improved significantly on both TYP and TYP-R with no significant difference between them. Early responders were defined as patients whose PANSS change scores were greater than the median. Twenty-two single nucleotide polymorphisms (SNPs) were analysed in five DRIP-encoding genes. Two SNPs in NEF3, which encodes the DRIP, neurofilament-medium (NF-M), were associated with early response (rs1457266, p=0.01; rs1379357, p=0.006). A 5 SNP haplotype spanning NEF3 was over-represented in early responders (p=0.015), in the combined patient group and in the TYP group alone. These findings suggest that variation in NEF3, most likely functional variants that are in linkage disequilibrium with the SNPs that we studied, influences rate of response to TYP. Since NEF3 is primarily associated with dopamine D1 receptor function, the evidence for a complementary role of dopamine D1 receptors in antipsychotic effects is considered. The findings reported here open an interesting research avenue in the pharmacogenetics of antipsychotic effects but require replication in larger samples treated in a controlled context.