Mentor
Dr. Lori Wallrath
Participation year
2011
Project title

Modeling Emery-Dreifuss Muscular Dystrophy in Drosophila

Abstract

Autosomal Dominant Emery-Dreifuss muscular dystrophy (AD-EDMD) is an inherited form of muscle disease that affects ~1/100,000 individuals. It is characterized by childhood onset of muscle weakness and wasting, early joint contractures and adult cardiac disease. Currently, there are no treatments for the disease. AD-EDMD is one of twelve diseases that are caused by mutations in the LMNA gene encoding A-type lamins. Lamins are intermediate filament proteins that play a role in both the determination of the nuclear structure and the regulation of gene expression. It is unknown whether the muscle defects cause malfunctioning of the neuro-muscular junction (NMJ). To address this issue, we are suing a Drosophila (fruit fly) model for AD-EDMD that was developed in our laboratory. Muscle-specific expression of mutant lamins, modeled after those causing disease, give rise to locomotion defects and eventually death. Using this model, we have used immunohistochemistry to examin the localization of key molecules involved in muscle-nerve communication. Larvae expressing wild type and mutant lamins were dissected, fixed and stained with antibodies that recognize synapsin (Syn), Bruchpilot (Brp) and Disc Large (Dlg). Syn binds acetylcholine vesicles, Brp densely surrounds the T-bar, an active zone at the NMJ, and Dlg is required for proper structure at the NMJ. Larvae expressing wild type lamin showed the anticipated staining pattern for all antibodies. In contrast, larvae expressing mutant forms of lamin showed mislocalization of the markers suggesting a post-synaptic defect. Results from these studies strongly suggest that mutant lamins cause neuro-muscular junction defects and that drugs used to treat NMJ defects might be a possible treatment for AD-EDMD patients.

Juan  Castillo Tavarez
Education
University of Iowa