Mutations in the human LMNA gene encoding A-type lamins give rise to a broad spectrum of diseases termed laminopathies. This proposal focuses on laminopathies in which muscle tissue is affected. Lamins are filament proteins that make up a network that line the inner side of the nuclear envelope. We discovered that mutant lamins cause aggregates of nuclear envelope proteins to accumulate in the cytoplasm of muscle fibers. This was observed in both human muscle biopsy tissues and muscle from our Drosophila model of laminopathies. Using the Drosophila model, we discovered that genes involved in cellular detoxification are enriched among those dramatically up-regulated in early stages of disease pathology. In addition, we discovered that mutant lamins cause an atypical metabolic state in muscle termed 'reductive stress'. Based on these observations, we hypothesize that cytoplasmic aggregation of nuclear envelope proteins cause the induction of anti-oxidant gene expression that alters the redox status of muscle, contributing to disease pathology.
Two specific aims are proposed to test this hypothesis.
Specific Aim 1 will determine the role of cytoplasmic aggregation of nuclear envelope proteins in the activation of anti-oxidant gene expression. This will be accomplished by regulating the metabolism of protein aggregates and assaying for changes in anti-oxidant gene expression and suppression of muscle phenotypes.
Specific Aim 2 will determine the role of reductive stress in muscle laminopathies. This will be accomplished by modulating the reducing equivalents in muscle fibers and assaying for suppression of muscle phenotypes. Taken together, our findings will determine the role of cytoplasmic aggregates and reductive stress in muscle disease pathology. In addition, we will identify compounds that suppress the muscle phenotypes as potential therapeutics.
Mutations in the human LMNA gene cause diseases known as laminopathies that include several types of muscular dystrophy and cardiomyopathy. It is not known how these mutations cause disease. The proposed research combines the expertise of basic research scientists and clinicians and builds on their novel discoveries. The results will provide insights on disease mechanisms and identify potential therapies.
|Bohnekamp, Jens; Cryderman, Diane E; Paululat, Achim et al. (2015) A Drosophila Model of Epidermolysis Bullosa Simplex. J Invest Dermatol 135:2031-9|