Kurzfassung

Studies with siRNA and antisense oligonucleotides have shown that the amount of mutant protein fundamentally influences the disease phenotype in proteinopathies caused by CAG repeat expansions. In this consortium we will use the ratio between mutant protein to mRNA as a measure for the translation and degradation efficiency of polyQ expanded protein. We will work out how this ratio correlates to the age of onset and the disease progression in patients with HD and SCA and mouse models and will...Studies with siRNA and antisense oligonucleotides have shown that the amount of mutant protein fundamentally influences the disease phenotype in proteinopathies caused by CAG repeat expansions. In this consortium we will use the ratio between mutant protein to mRNA as a measure for the translation and degradation efficiency of polyQ expanded protein. We will work out how this ratio correlates to the age of onset and the disease progression in patients with HD and SCA and mouse models and will establish it as a prognostic biomarker. In a set of different approaches in yeast, mouse mutants and patients we will furthermore search for endogenous factors that regulate the expression of polyQ expanded protein and thereby modify the disease phenotype. From these data we will extract a genetic signature for the clinical variability of these diseases. Finally we will use a recently identified protein complex, the MID1 protein complex, that controls the translation efficiency of mRNAs containing CAG repeat expansions as a promising drug target and will screen an FDA approved library for molecules that disturb this mechanism and inhibit the synthesis of polyQ expanded protein. Together with metformin and resveratrol, that we have shown previously to interfere with the MID1 protein complex, identified compounds will be tested in cell culture and animal models for their potential to be used as a causative therapy aiming at the reduction of disease making protein in CAG repeat expansion disorders.» weiterlesen» einklappen