The general aim of this project is to test the hypothesis that movement of neurofilaments relative to microtubules can be achieved by an ATP-dependent molecule linked to the neurofilament and moving along the microtubules. Neurofilaments are the most abundant intermediate filament type expressed in neurons and are characterized by long sidearm extensions orthogonal to the filament axis that are thought to link neurofilaments to microtubules and other intracellular structures. Neurofilaments in vivo are presumed to provide mechanical stability to the neuron by forming a viscoelastic network characterized by higher resistance to mechanical stress than provided by other cytoskeletal polymers. A second potential cellular function of neurofilaments is to facilitate or organize transport of materials, including microtubules, through the neuron, especially during the slow axonal transport required for neuronal growth, differentiation, and function. The molecular mechanism of slow axonal transport is unknown, but neurofilaments, microtubules, and the microtubule motor dynein are all implicated in this process. This proposal combines in vitro biophysical, biochemical, and cell biologic studies to characterize a novel form of motility in which individual neurofilaments move along microtubules by a mechanism involving cytoplasmic dynein and perhaps other motor proteins. Since dysfunction or loss of neurofilaments is associated with several neuronal pathologies such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, and neurodegeneration with aging, these studies may reveal molecular interactions that can be targets for neuronal disease prevention or therapy.
| Didonna, B A; Lubensky, T C (2005) Nonaffine correlations in random elastic media. Phys Rev E Stat Nonlin Soft Matter Phys 72:066619 |
| Wagner, Oliver I; Ascano, Jennifer; Tokito, Mariko et al. (2004) The interaction of neurofilaments with the microtubule motor cytoplasmic dynein. Mol Biol Cell 15:5092-100 |
| Rajasalu, Tarvo; Teesalu, Kaupo; Janmey, Paul A et al. (2004) Demonstration of natural autoantibodies against the neurofilament protein alpha-internexin in sera of patients with endocrine autoimmunity and healthy individuals. Immunol Lett 94:153-60 |
| Hough, L A; Islam, M F; Janmey, P A et al. (2004) Viscoelasticity of single wall carbon nanotube suspensions. Phys Rev Lett 93:168102 |
| Wagner, O I; Lifshitz, J; Janmey, P A et al. (2003) Mechanisms of mitochondria-neurofilament interactions. J Neurosci 23:9046-58 |
| Tang, Jay X; Janmey, Paul A; Lyubartsev, Alexander et al. (2002) Metal ion-induced lateral aggregation of filamentous viruses fd and M13. Biophys J 83:566-81 |
| Flanagan, Lisa A; Ju, Yo-El; Marg, Beatrice et al. (2002) Neurite branching on deformable substrates. Neuroreport 13:2411-5 |
| Aranda-Espinoza, Helim; Carl, Philippe; Leterrier, Jean Francois et al. (2002) Domain unfolding in neurofilament sidearms: effects of phosphorylation and ATP. FEBS Lett 531:397-401 |
| LaMonte, Bernadette H; Wallace, Karen E; Holloway, Beth A et al. (2002) Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron 34:715-27 |
