Richard Nass, Ph.D.
Associate Professor, Pharmacology and Toxicology
Ph.D: The Johns Hopkins University School of Medicine (1998)
Molecular Mechanisms involved in Parkinson's Disease and Dopamine Neurodegeneration; Identification of Novel Therapeutic Leads that can Inhibit Dopamine Neuron Degeneration.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder and is characterized by the irreversible loss of dopamine (DA) neurons in the substantia nigra pars compacta. Despite its high prevalence and over 40 years of intense investigations into the disorder, the molecular determinants involved in the etiology of the disease remain elusive. A significant hindrance in identifying the molecular components involved in DA neurodegeneration is the limitations of mammalian models to incorporate in vivo genetic and chemical strategies in the search for endogenous molecules and pharmaceuticals that could be involved in, or could protect against, the neurodegeneration. We developed a novel pharmacogenetic model system using the nematode Caenorhabditis elegans (C. elegans) to explore the molecular basis of DA neuron degeneration in vivo. This work resulted in the generation of the first C. elegans Parkinson's disease model, and allowed for the first time the opportunity to visualize DA neurons clearly in a living animal. We are exploiting this system to identify and characterize the molecular determinants involved in DA neurodegeneration. My laboratory addresses the following fundamental questions:
1) What are the molecular components involved in DA neuron cell death?
2) What are the endogenous molecules involved in manganese and other
heavy metal-induced neurodegeneration?
3) What role do mitochondria play in DA neuron toxin vulnerability?
4) How do PD-associated proteins contribute to DA neuron viability and
5) Can we develop high-throughput chemical and genetic screens to
identify endogenous molecules and xenobiotics involved in
neurodegeneration and neuroprotection?
To answer these questions we have undertaken a cellular, genetic, and molecular analysis of DA neuron degeneration in the nematode C. elegans. C. elegans is particularly advan¬tageous for genetic studies because it is easily propagated, and because the genetic and physical maps of its genome are well-characterized. In addition, the C. elegans nervous system, including the DA neurons, is highly conserved on the molecular level with mammals. We are taking a targeted gene approach and utilizing the power of forward genetics in the nematode to identify genes involved in DA neurodegeneration. We are also establishing facile, in vivo high-throughput screening (HTS) platforms to identify molecules that enhance (e.g., pesticides) or protect (pharmaceutical leads) against DA neuron cell death. Furthermore, we are developing suppressor screens to identify and characterize the pathways targeted by these compounds.
Nass, R. and Przedborski, S., ed., Parkinson's disease: pathogenic and therapeutic insights from toxin and genetic models. Reference Book, Elsevier Academic Press. Expected release date: Summer 2008
Nass, R., Chen, L. (2007) C. elegans models of human neurodegenerative diseases: a powerful tool to identify molecular mechanisms and novel therapeutic targets. In: Sourcebook of Model Organisms in Biomedical Research, ed. P.M. Conn. Humana Press. Manuscript in press.
Nass, R., Nichols, CD. (2007) Invertebrates as powerful genetic models for human neurodegenerative diseases. In: Handbook of Contemporary Neuropharmacology, ed. David Sibley, Israel Hanin, and Michael Kuhar. John Wiley and Sons, 567-588
Nass, R., Hamza, I. (2007) The nematode C. elegans as a model to explore toxicology in vivo: solid and axenic growth culture conditions and compound exposure parameters, Curr Protocols Toxicology, 1.9.1-1.9.18
Jiang, GC-T., Tidwell, K., McLaughlin, B., Cai, J., Gupta, Milatovic, D., Nass, R., Aschner (2007) Neurotoxic potential of depleted uranium - effects in primary corticoal neuron cultures and in Caenorhabditis elegans. Toxicol Sci, 99:553-565
Vartiainen, S., Pehkonen, P., Lakso, M., Nass, R., Wong, G. (2006) Identification of gene expression changes in transgenic C. elegans overexpressing human alpha-synuclein. Neurobio. Dis. 22:477-486
Asikainen, S., Vartianinen, S., Lakso, M., Nass, R. Wong, G. (2005) Selective sensitivity of Caenorhabditis elegans neurons to RNA interference. Neuroreport 17:230-231
Nass, R., Hahn, M., Jessen, T., McDonald, P., Carvelli, L., Blakely, RD (2005) A genetic screen in C. elegans for dopamine neuron insensitivity to 6-hydroxydopamine identifies dopamine transporter mutants impacting transporter biosynthesis and trafficking. J. Neurochem. 94:774-785