Whole gene expression profile in blood reveals multiple pathways deregulation in R6/2 mouse model

Abstract

BackgroundHuntington Disease (HD) is a progressive neurological disorder, with pathological manifestations in brain areas and in periphery caused by the ubiquitous expression of mutant Huntingtin protein. Transcriptional dysregulation is considered a key molecular mechanism responsible of HD pathogenesis but, although numerous studies investigated mRNA alterations in HD, so far none evaluated a whole gene expression profile in blood of R6/2 mouse model.FindingsTo discover novel pathogenic mechanisms and potential peripheral biomarkers useful to monitor disease progression or drug efficacy, a microarray study was performed in blood of R6/2 at manifest stage and wild type littermate mice. This approach allowed to propose new peripheral molecular processes involved in HD and to suggest different panels of candidate biomarkers. Among the discovered deregulated processes, we focused on specific ones: complement and coagulation cascades, PPAR signaling, cardiac muscle contraction, and dilated cardiomyopathy pathways. Selected genes derived from these pathways were additionally investigated in other accessible tissues to validate these matrices as source of biomarkers, and in brain, to link central and peripheral disease manifestations.ConclusionsOur findings validated the skeletal muscle as suitable source to investigate peripheral transcriptional alterations in HD and supported the hypothesis that immunological alteration may contribute to neurological degeneration. Moreover, the identification of altered signaling in mouse blood enforce R6/2 transgenic mouse as a powerful HD model while suggesting novel disease biomarkers for pre-clinical investigation.

Bioinformatics method identifies potential biomarkers of dilated cardiomyopathy in a human induced pluripotent stem cell-derived cardiomyocyte model

“…Intergrins are known as the major receptors for substantial ECM-mediated cellular activities, including cell adhesion, cell proliferation and differentiation (33). Enrichment analysis in a mouse model has indicated that integrins, such as ITGB6, can participate in the DCM pathway (34). The findings of the present study indicated that the DEG ITGB6 in DCM was significantly enriched in the ECM-receptor interaction pathway.…”

Safety, pharmacokinetics, pharmacogenomics and QT concentration−effect modelling of the SirT1 inhibitor selisistat in healthy volunteers

“…These genes are involved in mechanisms of signal transduction and transmembrane transport (TMCC3, LDLR, CLIC3, PRKAR1A, USP10), in metabolic processes related to cholesterol, lipid and steroid homeostasis (LDLR, AKR1C3, ACBD3, TXNDC3, USP10) and redox processes (AKR1C3, TXNDC3). While this transcriptional signature may itself be useful as a target engagement marker, it also generates further hypotheses regarding the molecular mechanism of action of selisistat in HD, similarly to the work performed in the transgenic R6/2 HD mouse model [17] and also the possibility to develop target engagement or disease progression markers based on the relative gene products.…”

“…For CYP 2C8, 2D6, 2E1 and 3A4 (midazolam and testosterone sites), IC50 values were estimated to be higher than 100 μM. For CYP 1A2, 2C9 and 2C19, calculated IC50 values of 8.7, 62.4 and 72.2 μM were determined, respectively [17]. Selisistat is therefore unlikely to exhibit clinically significant CYP-mediated drug-drug interactions with compounds metabolized by CYP 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 at the expected plasma concentrations, whereas interactions with compounds primarily or exclusively metabolized by CYP 1A2 cannot be excluded at pharmacologically relevant plasma concentrations.…”

Transcription, Epigenetics and Ameliorative Strategies in Huntington’s Disease: a Genome-Wide Perspective

“…HD mouse models in which the mHtt transgene was designed to reproduce the ubiquitous expression pattern of the endogenous Htt [ 48 ] show altered transcriptomes in the retina [ 26 ] and in nonneuronal tissues, such as blood [ 49 ] and muscle [ 23 , 25 ], in the latter case with apparently little contributions of diabetes and weight loss. Peripheral tissues facilitate access to biomaterial and open the possibility of their use in the identification of biomarkers.…”