Molecular Chaperones as A Therapeutic Approach to Huntington’s Disease
Molecular Chaperones as A Therapeutic Approach to Huntington’s Disease

Summary/Abstract: Neuronal cell death in subpopulations of brains affected by Huntington’s disease has beentheorised to be due to cell cytotoxicity. The cause of this cytotoxicity, however, is not yet known.One mutant allele of the Huntingtin gene is sufficient to cause the disorder through the synthesisof the Huntingtin protein. Despite the ubiquitous expression of the HTT gene, expansion of thepolyglutamine (polyQ) tract in HTT leads to progressive cell death in affected brains,predominantly in the basal ganglia. The polyQ of the protein expressed when this mutant gene istranslated has shown to increase the chance of protein aggregates forming. In the Centre forGenomic Regulation, the transformation and study of S.cerevisiae cells have demonstrated apositive correlation between the number of polyQ repeats and the number of protein aggregatesthat develop within cells. This was evident in the Western Blot and confocal microscopic images.An extra protein band in the Western Blot indicated protein aggregation in the well with thehighest number of CAG repeats, implying that with more repeats, the higher the propensity foraggregation. The growth observed in these cells was slower, indicating the inextricable linkbetween aggregation and cytotoxicity within cells. The detrimental effect of protein aggregationis known, therefore the methods that will be proposed will consist of preventing or reducingprotein aggregation within cells. HTT is a functional protein, essential to brain development andneuronal survival and thus, by targeting only the aggregates, the functionality of the protein isnot affected. Harnessing the essential role of molecular chaperones in promoting the refolding ofproteins within cells will form the main body in discussing a therapeutic approach toHuntington’s disease; by studying the aggregation propensity in different concentrations of amolecular chaperone, the effectiveness of the molecule can be investigated. Following the results,a discussion on how effectively this method combats aggregation will follow. This discussiondepends on the cytotoxicity that remains in the cells studied.

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