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For this reason, transcriptional and behavioral alterations have been intensely studied in R6/2, which has being commonly employed not only in pre-clinical drug testing but also in peripheral investigations, often realized in parallel with HD patients. R6/2 is one of the first HD transgenic mouse model created, expressing only the N-terminal fragment of HTT (exon 1) and it is characterized by short survival and development of pathological features mimicking human stages of disease. Numerous behavioral and neurological symptoms similar to what seen in HD patients have been also observed in transgenic mouse models including those expressing only short fragments of mut-HTT, as R6/2 mice.
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Įven though no animal models currently in use encompass all disease features, transgenic mice carrying either full length or mut-HTT fragments represent an invaluable instrument to study pathological mechanisms and to test efficacy and toxicity of small molecules in pre-clinical settings. Mutant Huntingtin protein (mut-HTT) and its aggregates could modulate gene transcription by entering the nucleus and altering the transcriptional machinery either directly, through DNA binding, or sequestering important transcription factors. Striking evidences support an important role of transcriptional abnormalities in HD pathogenesis. The aberrant polyQ tract results in Huntingtin protein misfolding, which generates insoluble intracellular inclusions and aggregates, important hallmarks of the disease.ĭespite extraordinary efforts in understanding the HD pathogenesis, the exact molecular mechanisms responsible for this devastating disorder are still unknown and probably multiple parallel processes may contribute, representing potential therapeutic targets. In healthy individuals, CAG number is included in the range of 6 to 26, while HD patients have more than 36 Gln stretch with an inverse relationship between polyQ length and the age of onset. The cause of this fatal disease is an aberrant expansion of CAG trinucleotide in the exon 1 of HTT gene, translating into a polyglutamine tract (polyQ) at the N-terminus, and conferring gain-of-function and loss-of-function to wild type huntingtin protein. Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive atrophy of specific brain areas with consequent alterations of motor and cognitive functions, including psychiatric disturbances, weight loss, as well as metabolic, neuroendocrine and immunological alterations.
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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.
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Our 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. 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. Among the discovered deregulated processes, we focused on specific ones: complement and coagulation cascades, PPAR signaling, cardiac muscle contraction, and dilated cardiomyopathy pathways. This approach allowed to propose new peripheral molecular processes involved in HD and to suggest different panels of candidate biomarkers. To 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. 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. Huntington 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.