JEANNE M. FREDERICK
|Research Assistant Professor of Ophthalmology & Visual Sciences
Neurobiology of Disease
GOAL: To investigate the pathogenesis of mutant protein expression in retina neurons
We study the organization of the retina in health and disease. Toward this end, the phenotypes of transgenic and knockout/ knock-in mice carrying mutations in genes linked to retina dystrophies are analyzed. We are particularly interested in signal transduction, remodeling of the inner retina subsequent to rod and cone photoreceptor degeneration, and mechanisms that lead to cell death. In several neurodegenerative diseases, unfolded proteins accumulate intracellularly as insoluble inclusions and may serve a critical role in disease progression. If native polypeptide conformations are lost through genetic mutation or postsynthetic damage (e.g., environmental stress), cells normally have elaborate mechanisms to prevent the aggregation of unfolded proteins, to attempt refolding and, if proper folding is impossible, to degrade the abnormal polypeptides into amino acids.
However, we have shown that in a mouse model for human adRP (autosomal dominant retinitis pigmentosa), expression of a mutant rhodopsin (visual pigment) generates a protein that fails to mature, transport and support normal rod photoreceptor outer segment formation and, moreover, is cytotoxic. The mutant protein folds incorrectly and is retained in the endoplasmic reticulum thereby initiating an unfolded protein response. What is the link between expression of a misfolded, mutant protein and induction of cell death? To address such questions, we employ gene cloning, bright-field and confocal microscopy and related techniques in cell and molecular biology. For an example, see the recent publication:
Neale, B.M., Fagerness, J., Reynolds, R., Sobrin, L., Parker, M., Raychaudhuri, S., Tan, P.L., Oh, E.C., Merriam, J.E., Souied, E., Bernstein, P.S., Li, B., Frederick, J.M., Zhang, K., Brantley, M.A. Jr, Lee, A.Y., Zack, D.J., Campochiaro, B., Campochiaro, P., Ripke, S., Smith, R.T., Barile, G.R., Katsanis, N., Allikmets, R., Daly, M.J., and Seddon, J.M. (2010) Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci USA, Apr 20;107(16):7395-7400. Epub 2010 Apr 12. PubMed PMID: 20385826.
Kirschman, L.T., Kolandaivelu, S., Frederick, J.M., Dang, L., Goldberg, A.F., Baehr, W., and Ramamurthy, V. (2010) The Leber congenital amaurosis protein, AIPL1, is needed for the viability and functioning of cone photoreceptor cells. Hum Mol Genet, Mar 15;19(6):1076-87. Epub 2009 Dec 30. PubMed PMID: 20042464.
Karan, S., Frederick, J.M., and Baehr, W. (2010) Novel functions of photoreceptor guanylate cyclases revealed by targeted deletion. Mol Cell Biochem, Jan;334(1-2):141-55. Epub 2009 Dec 9. Review. PubMed PMID: 20012162.
Avasthi, P., Watt, C.B., Williams, D.S., Le, Y.Z., Li, S., Chen, C.K., Marc, R.E., Frederick, J.M., and Baehr, W. (2009) Trafficking of membrane proteins to cone but not rod outer segments is dependent on heterotrimeric kinesin-II. J Neurosci, Nov 11;29(45):14287-98. PubMed PMID: 19906976.
Bhosale, P., Li, B., Sharifzadeh, M., Gellermann, W., Frederick, J.M., Tsuchida, K., and Bernstein, P.S. (2009) Purification and partial characterization of a lutein-binding protein from human retina. Biochemistry, Jun 9;48(22):4798-807. PubMed PMID:19402606.
Baehr, W., and Frederick, J.M. (2009) Naturally occurring animal models with outer retina phenotypes. Vision Res, Nov;49(22):2636-52. Epub 2009 Apr 16. Review. PubMed PMID: 19375447.
Baehr, W., Karan, S., Maeda, T., Luo. D-G., Li, S., Bronson, J.D., Yau, K-W., Frederick, J.M., and Palczewski, K. (2007) The functions of guanylate cyclase 1 (GC1) and guanylate cyclase 2 (GC2) in rod and cone photoreceptors. J. Biol. Chem., 12:8837-8847.
Baehr, W., and Frederick, J. M. (2001) Inherited retina diseases: vertebrate animal models. Encyclopedia of Life Sciences, MacMillan Reference Ltd., in press.
Frederick, J. M., Krasnoperova, N., Hoffmann, K., Church-Kopish, J., Rüther, K., Howes, K., Lem, J., and Baehr, W. (2001) Mutant rhodopsin transgene expression on a null background. Invest. Ophthalmol. & Visual Science 42:826-833.
Frederick, J., Bronson, J. D., and Baehr, W. (2000) Animal models for inherited retinal diseases. In "Vertebrate Phototransduction and the Visual Cycle." Methods in Enzymology 316:515-526.