1/9/2024 0 Comments Theine hundincton deseaseThe ability to explore PolyQ-associated mechanisms of cardiomyopathy in a genetically tractable whole organism, Drosophila melanogaster, promises to provide novel insights into the relationship between amyloid accumulation and heart dysfunction. Modulation of protein folding and oxidative stress pathways in this system reduced the number of aggregates and reversed the cardiac dysfunction in response to expression of disease-causing PolyQ. We have developed a novel Drosophila heart model that exhibits significant GFP-positive aggregates upon HD-causing PolyQ expression in myocardial cells resulting in PolyQ length-dependent physiological defects. However, the mechanisms by which disease-causing poly-glutamine repeats (PolyQ) cause heart dysfunction in these patients are unclear. Recent studies suggest that HD patients show increased susceptibility to cardiac failure. Huntington's disease (HD) is associated with amyloid-like inclusions in the brain and heart, and accumulation of amyloid protein is associated with neurodegeneration and cardiomyopathy. We conclude that modulation of both protein unfolding and oxidative stress pathways in the Drosophila heart model can ameliorate the detrimental PolyQ effects, thus providing unique insights into the genetic mechanisms underlying amyloid-induced cardiac failure in HD patients. Our results demonstrate that mutant-PolyQ induces aggregates, disrupts the sarcomeric organization of contractile proteins, leads to mitochondrial dysfunction and increases oxidative stress in cardiomyocytes leading to abnormal cardiac function. Moreover, co-expression of both UNC-45 and SOD more efficiently suppressed GFP-positive aggregates, myofibrillar disorganization and physiological cardiac defects induced by PolyQ-72 than did either treatment alone. However, co-expression of UNC-45 dramatically suppressed PolyQ-72 induced aggregation and partially suppressed myofibrillar disorganization. Co-expression of SOD suppressed PolyQ-72 induced mitochondrial defects and partially suppressed aggregation as well as myofibrillar disorganization. To further confirm the involvement of oxidative stress or protein unfolding and to understand the mechanism of PolyQ induced cardiomyopathy, we co-expressed expanded PolyQ-72 with the antioxidant superoxide dismutase (SOD) or the myosin chaperone UNC-45. Cardiac-specific expression of disease causing Poly-Q also shortens lifespan of flies dramatically. Structural and ultrastructural analysis of the myocardial cells revealed reduced myofibrillar content, myofibrillar disorganization, mitochondrial defects and the presence of PolyQ-GFP positive aggregates. Cardiac expression of GFP-tagged Htt-PolyQs resulted in PolyQ length-dependent functional defects that included increased incidence of arrhythmias and extreme cardiac dilation, accompanied by a significant decrease in contractility. We have generated a Drosophila model of cardiac amyloidosis that exhibits accumulation of PolyQ aggregates and oxidative stress in myocardial cells, upon heart-specific expression of Huntingtin protein fragments (Htt-PolyQ) with disease-causing poly-glutamine repeats (PolyQ-46, PolyQ-72, and PolyQ-102). HD patients exhibit a high incidence of cardiovascular events, presumably as a result of accumulation of toxic amyloid-like inclusions. Amyloid-like inclusions have been associated with Huntington's disease (HD), which is caused by expanded polyglutamine repeats in the Huntingtin protein.
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