Scanning for intensely fluorescent targets (SIFT): a new tool to study pathological protein aggregate formation in MFM and its reversal through pharmacologic intervention

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We aim to elucidate the mechanisms leading to pathological protein aggregation and muscle pathology in myofibrillar myopathies due to mutations in MFM causing genes. As a novel approach, we will use multi-color confocal single-particle spectroscopy methods such as scanning for intensely fluorescing targets (SIFT) to analyze protein aggregates of desmin mutants and other MFM-associated proteins, which have previously been characterized by transfection and in vitro assembly studies. The focus will be the characterization of pathological protein aggregates in regard to formation, molecular architecture, and homologeous as well as heterologeous protein-protein interactions in living cells and at the single-molecule level. Therapeutic perspectives are addressed by testing novel compounds directly targeting pathological protein oligomers, allelle-specific knock-down, heat shock protein inducers, and compounds affecting aggregate clearance by autophagy and proteasomal metabolism.