Mutations in dysferlin cause muscular dystrophy, and the mechanism by which loss of dysferlin leads to muscular dystrophy is a fundamentally different than other forms of muscular dystrophy. Dysferlin is a membrane-associated protein that participates in vesicle trafficking events. In muscle this includes vesicle movement important for plasma membrane repair. Our work has also shown that dysferlin, like other members of the ferlin family, regulates vesicle recycling. We characterized myoferlin and Fer1L5, two highly related proteins to dysferlin to understand whether these proteins have overlapping function to substitute for dysferlin. These ferlin proteins each have at least six C2 domains, domains important for protein-membrane and protein-protein interactions. We identified that the first C2 domain of dysferlin binds negatively charged phospholipids in a calcium sensitive manner. We subsequently showed that ferlin C2 domains bind directly to carboxy-terminal Eps 15 Homology Domain (EHD) proteins, and that EHD proteins are required for ferlin intracellular trafficking. EHD proteins can induce tubule formation in vitro and in cell. We will study the interaction between ferlins, EHD, and Bin1 in the genesis of transverse tubule in muscle. We will then examine the mechanisms by which loss of ferlin proteins renders the muscle susceptible to detubulation and the molecular requirements to restore tubule formation and function. Finally, we will examine recycling events mediated by ferlin proteins. In each step, we will determine the domains of dysferlin, or the related myoferlin and Fer1L5 that mediate these events and assess whether restoration of these functions corrects the underlying pathology in dysferlin-associated muscular dystrophy.
Mutations in dysferlin lead to Limb Girdle Muscular Dystrophy. Although this form of disease is not common, the pathway by which dysferlin works in muscle may be very important for muscle growth during development and during muscle repair. Even in normal individuals muscle mass declines with age and recovery from injury is slower. Understanding dysferlin action in muscle will shed light on mechanisms by which we can improve muscle disease and muscle mass.
|Lamar, Kay-Marie; Miller, Tamari; Dellefave-Castillo, Lisa et al. (2016) Genotype-Specific Interaction of Latent TGFÎ² Binding Protein 4 with TGFÎ². PLoS One 11:e0150358|
|Demonbreun, Alexis R; Allen, Madison V; Warner, James L et al. (2016) Enhanced Muscular Dystrophy from Loss of Dysferlin Is Accompanied by Impaired Annexin A6 Translocation after Sarcolemmal Disruption. Am J Pathol 186:1610-22|
|Demonbreun, Alexis R; Quattrocelli, Mattia; Barefield, David Y et al. (2016) An actin-dependent annexin complex mediates plasma membrane repair in muscle. J Cell Biol 213:705-18|
|Demonbreun, Alexis R; McNally, Elizabeth M (2016) Plasma Membrane Repair inÂ Health and Disease. Curr Top Membr 77:67-96|
|Lenhart, Kaitlin C; O'Neill 4th, Thomas J; Cheng, Zhaokang et al. (2015) GRAF1 deficiency blunts sarcolemmal injury repair and exacerbates cardiac and skeletal muscle pathology in dystrophin-deficient mice. Skelet Muscle 5:27|
|Demonbreun, Alexis R; McNally, Elizabeth M (2015) DNA Electroporation, Isolation and Imaging of Myofibers. J Vis Exp :e53551|
|Demonbreun, Alexis R; Swanson, Kaitlin E; Rossi, Ann E et al. (2015) Eps 15 Homology Domain (EHD)-1 Remodels Transverse Tubules in Skeletal Muscle. PLoS One 10:e0136679|
|Demonbreun, Alexis R; Biersmith, Bridget H; McNally, Elizabeth M (2015) Membrane fusion in muscle development and repair. Semin Cell Dev Biol 45:48-56|
|Ferlini, Alessandra; Flanigan, Kevin M; Lochmuller, Hanns et al. (2015) 204th ENMC International Workshop on Biomarkers in Duchenne Muscular Dystrophy 24-26 January 2014, Naarden, The Netherlands. Neuromuscul Disord 25:184-98|
|Gao, Quan Q; Wyatt, Eugene; Goldstein, Jeff A et al. (2015) Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping. J Clin Invest 125:4186-95|
Showing the most recent 10 out of 26 publications