facilitate the identification of mRNA targets for the 5 PGRN FTLD TDP associated miRNAs, we made use of publicly available Affymetrix mRNA arrays performed in FTLD TDP patients with and without PGRN mutations. Since all 5 miRNAs were upregulated in frontal cortex and cerebellum Cabozantinib cancer of PGRN mutation carriers, we focused on mRNA targets which were downregulated in both frontal cortex and cerebellum of PGRN mutations car riers in the Affymetrix mRNA arrays. A total of 177 pro besets showed significant downregulated expression in both the cortex and cerebellum of the PGRN FTLD TDP patients. When compared with the list of TargetScan predicted genes for each of the 5 PGRN FTLD TDP associated miRNAs, 18 genes with anti correlated mRNA miRNA expression were identified.

Among the 18 genes, brain specific angiogen esis inhibitor 3, glycerol kinase and solute carrier family 23, member 2 were targeted by 3 of the 5 miRNAs upregulated in the cortex and cerebel lum of the PGRN FTLD TDP patients. Seven genes were targeted by 2 of the 5 miRNAs, and 8 genes were targeted by 1 of the 5 miRNAs. Next, for the 18 genes we found in common between the TargetScan and Affymetrix results, we examined their potential biological roles with Ingenuity Pathway analysis. Interestingly, neurological and cellular regula tions were the most prominently represented biological roles of the significant pathways identified. In fact, 6 of the genes, pro tein tyrosine phosphatase, receptor type, D, potassium voltage gated channel, shaker related subfam ily, beta member 1, cannabinoid receptor 1, alpha synuclein, and neural cell adhe sion molecule 1 were shown to have a specific role in behavioural responses, a phenotype which is con sistently altered in FTLD.

Discussion Identifying the molecular events leading to pathogenic outcomes in neurodegenerative diseases, such as FTLD, may ultimately produce new avenues for prevention or treatment of these disorders. In this study, we report a novel role for ncRNAs in the molecular profile of FTLD patients with genetic mutations in the secreted growth factor PGRN. The miRNA family of ncRNAs showed dis tinct expression patterns in post mortem brain tissue of FTLD TDP patients carrying loss of function mutations in PGRN compared to FTLD TDP patients without known mutations, suggesting that miRNAs are potential biomarkers and therapeutic targets for genetically linked dementia disorders.

Since the initial reports linking PGRN mutations to FTLD, the search for PGRN mediated signaling Entinostat cascades has intensified, such as the recently reported associations with sortilin. Through the comparison of ncRNA expression profiles from patients with genetic versus non genetic diagnosis of FTLD TDP, we aimed to identify new pathways which are under www.selleckchem.com/products/Bortezomib.html the control of PGRN signaling in vivo. Indeed, in frontal cortex samples of FTLD TDP patients, the expression of 3% of the detectable miRNAs from the expression arrays was significantly changed when PGRN and PGRN FTLD TDP