The objective of this proposal is to elucidate the role of the microtubule-associated protein, PTL-1, in the function and cytoarchitecture of mechanosensory neurons from Caenorhabditis elegans. The highly conserved family of structural microtubule- associated proteins, of which PTL-1 is the only member found in C. elegans, have been postulated to serve numerous functions in developing and adult neurons, including regulating the dynamics of microtubules and serving as dynamic cytoskeletal scaffolds for the protein assemblies involved in signal transduction. Dysfunction of these proteins in mammalian neurons has been implicated in neurodegenerative disorders like Alzheimer's disease and stroke, attesting to the importance of these proteins in neuron function. Little is known, however, about how these proteins are involved in these functions in healthy neurons. By utilizing the strengths of the genetics and the imaging capabilities of C. elegans, we will further our understanding of the role of this group of cytoskeletal proteins in neuron function. We will use genetic and behavioral strategies to determine the relationship between PTL-1 and the specialized microtubules found in mechanosensory neurons in adult nematodes. We will use confocal laser scanning microscopy and immunoprecipitation combined with genetic transformation techniques to reveal the protein-protein interactions of PTL-1 with these microtubules, as well as with components of the mechanosensory transduction machinery. By understanding how PTL-1 interacts with these proteins, we will gain a better understanding of the more general role of this family of proteins in healthy neurons, as well as a better appreciation of the evolutionary significance of this class of protein in neuron function. We will also further our understanding of the consequences of dysfunction of this class of protein as a result of disease or damage. One of the hallmark characteristics of stroke damage and Alzheimer's disease is the dysfunction of the structural microtubule-associated proteins, MAP2 and tau. The consequences of this dysfunction are unknown, because very little is known about how this important class of neuronal cytoskeletal protein functions in healthy neurons. This project will determine the function of one member of this family, PTL-1, in healthy neurons of the nematode, C. elegans, as a way of increasing our understanding of how this class of protein works in normal, healthy adult neurons, which will provide important clues as to the consequences to neurons of the dysfunction of these proteins in disease states. ? ?
| Gordon, Patricia; Hingula, Lee; Krasny, Michelle L et al. (2008) The invertebrate microtubule-associated protein PTL-1 functions in mechanosensation and development in Caenorhabditis elegans. Dev Genes Evol 218:541-51 |
