Cerebellar Predominant Increase in mRNA Expression Levels of Sirt1 and Sirt3 Isoforms in a Transgenic Mouse Model of Huntington's Disease.

The potential role of Sirt1 and Sirt2 subtypes of Sirtuins (class III NAD+-dependent deacetylases) in the pathogenesis of Huntington's disease (HD) has been extensively studied yielding some controversial results. However, data regarding the involvement of Sirt3 and their variants in HD are considerably limited. The aim of this study was to assess the expression pattern of Sirt1 and three Sirt3 mRNA isoforms (Sirt3-M1/2/3) in the striatum, cortex and cerebellum in respect of the effect of gender, age and the presence of the transgene using the N171-82Q transgenic mouse model of HD. Striatal, cortical and cerebellar Sirt1-Fl and Sirt3-M1/2/3 mRNA levels were measured in 8, 12 and 16 weeks old N171-82Q transgenic mice and in their wild-type littermates. Regarding the striatum and cortex, the presence of the transgene resulted in a significant increase in Sirt3-M3 and Sirt1 mRNA levels, respectively, whereas in case of the cerebellum the transgene resulted in increased expression of all the assessed subtypes and isoforms. Aging exerted minor influence on Sirt mRNA expression levels, both in transgene carriers and in their wild-type littermates, and there was no interaction between the presence of the transgene and aging. Furthermore, there was no difference between genders. The unequivocal cerebellar Sirtuin activation with presumed compensatory role suggests that the cerebellum might be another key player in HD in addition to the most severely affected striatum. The mitochondrially acting Sirt3 may serve as an interesting novel therapeutic target in this deleterious condition.

Assessment of risk factor variants of LRRK2, MAPT, SNCA and TCEANC2 genes in Hungarian sporadic Parkinson's disease patients.

INTRODUCTION: Parkinson's disease is the second most common neurodegenerative disease. Lifestyle, environmental effects and several genetic factors have been proposed to contribute to its development. Though the majority of PD cases do not have a family history of disease, genetic alterations are proposed to be present in 60 percent of the more common sporadic cases. OBJECTIVE: The aim of this study is to evaluate the frequency of PD related specific risk variants of LRRK2, MAPT, SNCA and PARK10 genes in the Hungarian population. Out of the ten investigated polymorphisms three are proposed to have protective effect and seven are putative risk factors. METHODS: For genotyping, TaqMan allelic discrimination and restriction fragment length polymorphism method was used. LRRK2 mutations were investigated among 124 sporadic PD patients and 128 healthy controls. MAPT and SNCA variant frequencies were evaluated in a group of 123 patients and 122 controls, while PARK10 variant was studied in groups of 121 patients and 113 controls. RESULTS: No significant difference could be detected in the frequencies of the investigated MAPT and PARK10 variants between the studied Hungarian PD cases and controls. The minor allele of the risk factor S1647T LRRK2 variant was found to be more frequent among healthy male individuals compared to patients. Moreover, in the frequency of one of the investigated SNCA variant a significant intergroup difference was detected. The minor allele (A) of rs356186 is proposed to be protective against developing the disease. In accord with data obtained in other populations, the AA genotype was significantly more frequent among Hungarian healthy controls compared to patients. Similarly, a significant difference in genotype distribution was also found in comparison of patients with late onset disease to healthy controls, which was due to the higher frequency of AG genotype among patients. CONCLUSION: The frequencies of different gene variants show great differences in populations. Assessment of the frequency of variants of PD related genes variants is important in order to uncover the pathomechanisms underlying the disease, and to identify potential therapeutic targets. This is the first comprehensive study focusing on these genetic variants in the population of East-Central European region. Our results extend the knowledge on the world wide occurrence of these polymorphisms by demonstrating the occurrence of specific alleles and absence of others in Hungarian PD patients.