Several human diseases are associated with the expression of mutated, misfolded and aggregation- prone amyloid proteins. Deposition of these amyloids, their proliferation or multimerization leads to the genesis of several neuropathies, including Alzheimer's and Huntington's diseases. Accumulation of amyloids in the human heart leads to cardiomyopathy. Despite several proteins being shown to be associated with cardiac amyloidosis, the precise mechanism that leads to the disease is poorly known. Recent evidence indicates that patients with Huntington's and Alzheimer's diseases demonstrate a greater occurrence of cardiovascular events but very little is known as to how these diseases lead to cardiac failure. Since many proteins are dependent on the cellular folding environment, we hypothesize that expression of HD- or AD-causing amyloids in the heart will disrupt the overall balance of protein folding quality control due to oxidative stress or global misfolding, resulting in loss of tissue function. To test our hypothesis, we will use the genetically tractable model organism Drosophila melanogaster and employ an integrative approach in exploration and suppression of cardiac amyloidosis. We propose to develop the first Drosophila model to investigate the cardiac defects associated with the accumulation of Alzheimer's and Huntington's disease-causing amyloid. Using the UAS-Gal4 expression system, we will express UAS-polyglutamine (for Huntington's) and UAS-A242 peptides (for Alzheimer's) in the Drosophila heart. We will examine the resulting cardiac defects at the physiological and cell biological levels. Furthermore, we will explore how expression of amyloid in the cardiac muscle afects expression of autophagy and other stress markers. We then plan to use genetic and pharmacological approaches to suppress cardiac amyloidosis. Genetic suppression of amyloids-induced cardiomyopathy will be attempted by over-expression of chaperones to reduce global protein unfolding or superoxide dismutase to ameliorate oxidative stress. We will also explore the effects of pharmacological agents such as chaperone inducers or antioxidants to ameliorate cardiac defects associated with amyloid accumulation. Our proposed study organism, Drosophila, with its high degree of gene conservation to the human genome and many techniques to manipulate its gene expression, will be an excellent model for exploring the mechanism of cardiac failure in Alzheimer's and Huntington's disease patients and may prove useful for developing therapies for human disease. Ultimately, once established, this model can be used for exploring genesis and suppression of cardiac amyloidosis linked with other amyloid precursor proteins. This proposal thus has broad applications and applies to cardiac, Alzheimer's and Huntington's diseases. All three diseases are devastating and the outcomes of this study may provide vital clues for their genesis.
Both Alzheimer's and Huntington's diseases are major risk factors for cardiac failure;the proposed study uses the model organism Drosophila melanogater for the first time to explore amyloid-induced cardiac dysfunction in these two major neurodegenerative diseases. We will use transgenic and pharmacological approaches for the suppression of the induced cardiac amyloidosis. This study is crucial for understanding the mechanism of cardiac failure in two major neuropathies and once established, this Drosophila model can be used to explore amyloid-induced cardiac failure associated with other amyloid precursor proteins.
|Trujillo, Adriana S; Ramos, Raul; Bodmer, Rolf et al. (2014) Drosophila as a potential model to ameliorate mutant Huntington-mediated cardiac amyloidosis. Rare Dis 2:e968003|
|Melkani, Girish C; Trujillo, Adriana S; Ramos, Raul et al. (2013) Huntington's disease induced cardiac amyloidosis is reversed by modulating protein folding and oxidative stress pathways in the Drosophila heart. PLoS Genet 9:e1004024|