A Drosophila melanogaster model for Understanding Human Sporadic-Inclusion Body Myositis



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Sporadic-Inclusion Body Myositis (s-IBM) is a muscle disease that is characterized by a slow-onset of weakness and atrophy in muscles of certain parts of the body. A specific protein present in patients with s-IBM called amyloid precursor protein (APP) and certain proteolytic fragments of APP serve as primary agents in pathogenesis. In order to understand the role of proteins responsible for pathogenesis, transgenic flies were bred to express wildtype human APP (hAPP) and presenilin. The intrinsic attributes of presenilin in the proteolytic processing of APP have adverse effects if alterations occur. A mutation in presenilin leads to an increase in Abeta production, resulting in the formation of aggregates, which triggers necrosis of the muscle cells. It was the aim of the study to investigate the effect of proteolytic fragments on sIBM. The accumulation of hAPP and proteolytic fragments Abeta40 and/or Abeta42 are a causative factor in sIBM and amyloid-related diseases such as Alzheimer s disease. These abnormal fragments are produced by transmembrane proteases, alpha-, beta-, and gamma-secretase. Alterations in secretase activity have been found to be a prime factor responsible for the production of these aggregates. Two proteins important in age-dependent neurodegeneration in the nervous system are the beta- secretase protein BACE and presenilin, found in the gamma-secretase protease complex. The goal of my research was to focus on the genetic factors that influence muscle degeneration in patients with sporadic-Inclusion Body Myositis (s-IBM) by exploring the interaction of presenilin in APP proteolysis in transgenic D. melanogaster. In my research I focused on behavioral changes due to the coexpression of mutant presenilin alleles with human APP in muscle cells. I hypothesized that the expression of mutant presenilin will affect the structure and function of muscles in D. melanogaster and therefore, exacerbate the symptoms of sporadic-Inclusion Body Myositis. Any stress that results in the onset of degeneration suggests that pathogenesis is muscle activity-dependent. To confirm that the presence of a mutation in presenilin genes causes degeneration in skeletal muscles, flies coexpressing mutant presenilin and hAPP were subjected to climbing and flight assays. The results allowed us to find differences among the wildtype and mutants so that conclusions could be made on the effect of hAPP on behavior. The significance of this work is to allow us to identify candidate targets for therapeutic intervention for the treatment of s-IBM.