Investigations into the effects of chaperone proteins on a drosophila model of machado-joseph disease (spinocerebellar ataxia type 3)

Polyglutamine (polyQ) diseases, a group of inherited neurodegenerative conditions including Huntington’s disease and Machado-Joseph Disease (MJD), arise from a CAG repeat beyond a healthy range, leading to a misfolded, non-functioning protein. These proteins tend to form aggregates, which may be responsible for the disease pathogenesis. Because the disease basis lies in misfolded protein, quality control chaperones, particularly HSP40, HSP70, and HSP90, are of special interest to researchers of the disease. The literature on the effects of HSP40 on rescue of degeneration and aggregate formation in polyQ diseases has been contentious, with researchers using a variety of models and both fly and human HSP40 unable to agree. This study examined the effects of up-regulated fly and human HSP40 on a full-length MJD model of Drosophila to allow comparison between the different versions of HSP40 and also with the various models in the literature, revealing a reduction in aggregates and rescue of degeneration by f-HSP40 but no rescue by h-HSP40. This study also examined the effects of altered HSP70 and HSP83 (the fly homolog of HSP90) expression on the progression of the disease, showing increased degeneration by down-regulated HSP70 and no apparent change by up-regulated HSP83 in healthy or disease flies