Fig. 1.
From: Synaptopathy, circuitopathy and the computational biology of Huntington’s disease
Pathogenic pathways in Huntington’s disease (HD) and the different levels at which modelling, computational approaches and systems biology might be applied to comprehensively understand pathogenesis and systematically identify therapeutic targets. HD is caused by a tandem repeat expansion mutation so that the trinucleotide (CAG) is expanded to become (CAG)n+x in the huntingtin gene. This tandem repeat tract is transcribed and translated to become a (Q)n+x polyglutamine tract in the huntingtin protein. This mutant protein leads to a cascade of molecular, cellular and systems changes which, together with the modulatory actions of genetic and environmental modifiers, ultimately lead to the onset of disease symptoms. By using more sophisticated approaches incorporating modelling, computational biology and systems neuroscience, we can obtain a more comprehensive and integrated understanding of the pathogenesis of HD, which will have major implications for therapeutic approaches aimed at preventing, treating and ultimately curing this devastating disease