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French

ID: <

10670/1.i0wjzc

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Where these data come from
Contribution of the transcriptome of peripheral blood mononuclear cells to the study of familial and sporadic cases with Parkinson's disease

Abstract

Parkinson's disease (PD) is prone to misdiagnosis particularly in the early stages. A better understanding of the deleterious mechanisms is essential to identify therapeutic targets and detect the disease earlier. Peripheral blood mononuclear cells (PBMCs) play a role in the deleterious cascade and reflect molecular events associated with PD. Moreover, the study of genetically determined forms of PD enables the identification of subjects at a very early. We hypothesized that PBMCs could be an interesting model to study some mechanisms reflecting the neurodegeneration even at an early stage of the disease. Therefore, we conducted transcriptomic studies in different groups of PD subjects or patients with mutations in order to detect deregulated genes and signaling pathways.We first studied the gene expression profile of PD subjects with the mutation G2019S of the LRRK2 gene. Analysis of microarrays identified disturbances in cell signaling pathways involved in PD. Alterations in the MAPK pathway, the actin cytoskeleton and vesicular transport, associated with the pathogenesis of LRRK2, were noted. The list of deregulated genes separates individuals based on their genetic status including an asymptomatic subject. G2019S LRRK2 mutation is associated to a particular gene expression profile identifiable in PBMCs even at early stage.Then we investigated another form of genetically determined by duplication of SNCA gene. We better characterized the relationship between genotype and clinical phenotype of the subjects. The duplication extends 4.928 Mb, contains 31 genes and results from non-allelic homologous recombination. The analysis of the expression of genes in the PBMCs of a subject carrying the mutation at preclinical stage showed overexpression of SNCA.We compared PBMCs gene expression of G2019S LRRK2 mutation carriers, SNCA duplication carrier and also sporadic PD patients. Our analysis showed that carriers of the LRRK2 mutation and sporadic PD patients have common deregulated signaling pathways that reflect the PD pathogenesis. By contrast, pathways deregulated in the subject with SNCA duplication reflect the pathogenesis of SNCA. In addition, we looked at the expression of SNCA isoforms in PBMCs of these three groups of individuals. Sporadic and LRRK2 patients showed a decreased expression of four isoforms of SNCA in their PBMCs. However, in the duplicated subject, only isoform 112 was overexpressed.Then we used this technology to identify molecular pathways associated with spino-cerebellar ataxia type 2 (SCA2), which provides rarely a parkinsonian phenotype and compared with subjects with a cerebellar phenotype. Again, we identified deregulation of gene expression associated with SCA2 pathogenesis, such as amyotrophic lateral sclerosis and actin cytoskeleton in PBMCs of subjects with parkinsonian and metabolism of RNA and inositol phosphate in cerebellar subjects.Finally, we looked at gene expression in PBMCs according to the evolutionary and clinical stage of PD including individuals at a very early. We compared their gene expression profiles with more advanced PD patients. From the early stages, we observed a deregulation of ERK/MAPK and PI3K/Akt pathways that control cell survival; these findings underscore the importance of these biological pathways in the development of PD.In conclusion, we demonstrated that PBMCs are an interesting model. The transcriptomic studies can get insight into the mechanisms associated with early stages of degeneration and into biological markers, such as SNCA. This technique could be applied in a larger number of subjects including other neurodegenerative diseases to detect specific diagnostic markers of PD.

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