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1109 Biomedical Research Bldg (BRB) II/III
Office: 215-573-8251
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Research Interest: We are exploring the genetic and cellular mechanisms of neurodegeneration. Protein folding is critically important for all life, from microbes to man. A bafflingly diverse set of cellular mechanisms has evolved to coordinate this exquisitely sensitive process. Not unexpectedly, problems in protein folding are the root cause of many of the most devastating diseases, which represent a major challenge to public health worldwide, especially as our population continues to age. Referred to collectively as protein misfolding disorders, these truly disastrous neurodegenerative diseases include Alzheimer’s disease, Parkinson’s disease and ALS (Lou Gehrig’s Disease). Understanding at a mechanistic level the cellular consequences of protein misfolding will help to suggest potential strategies for therapeutic intervention. We use baker’s yeast, Saccharomyces cerevisiae, as a model system to study the cell biology underpinning protein-misfolding diseases. Since dealing with misfolded proteins is an ancient problem, we hypothesize that the mechanisms employed to cope with them are likely conserved from yeast to man. Our long-term goal is to identify the critical genes and cellular pathways affected by misfolded human disease proteins. We have focused on the Parkinson’s Disease (PD) linked protein, α-synuclein: investigating both its role in pathology and its, as of yet elusive, normal function. By performing high-throughput genome-wide screens in yeast, we have identified a list of genes, many with clear human homologs, which are able to antagonize cellular toxicity associated with the accumulation of misfolded α-synuclein. Remarkably, some these genes are also able to rescue neuron loss in animal models of PD. A major focus of our future research will be the functional characterization of how these modifier genes interact with α-synuclein, with the goal to understand the critical cellular pathways affected by misfolded α-synuclein and how this contributes to neurodegeneration. Experiments are also underway to employ yeast cells as “living test tubes” to discover the, as of yet elusive, normal cellular function of a-synuclein. Encouraged by the power of the yeast system to gain insight into α-synuclein biology, we are creating new yeast models to study additional protein misfolding disorders, including Alzheimer’s disease and ALS. We plan to use these models to perform high-throughput genetic and small molecule screens to elucidate the molecular pathways that regulate the function of these disease proteins and control their conversion to a pathological conformation. We also have an active interest in the genetic cancer syndrome type 1 neurofibromatosis (NF1). Affecting 1 out of 4,000 births, NF1 is caused by loss-of-function mutations in neurofibromin, a Ras GTPase activating protein. Neurofibromin homologs are present in yeast, affording the opportunity to rapidly identify modulators of neurofibromin function. Accordingly, we have initiated studies to apply yeast genetics and our high-throughput screening infrastructure to explore the cellular pathways that become dysregulated in NF1. Finally, we are using zebrafish to explore the normal function of neurodegenerative disease proteins during development as well as to use live-cell imaging to visualize protein aggregation during neurodegeneration. Selected Publications: Gitler A.D., A. Chesi, M.L. Geddie, K.E. Strathearn, S. Hamamichi, K.J. Hill, K.A. Caldwell, G.A. Caldwell, A.A. Cooper, J.C-R. Rochet, and S. Lindquist (2009) α-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nature Genetics 41(3):308-315 Sun, Z. and A.D. Gitler (2008) Discovery and characterization of three novel synuclein genes in zebrafish. Developmental Dynamics 237:2490-2495. Johnson B.S., J.M. McCaffery, S. Lindquist, A.D. Gitler (2008) A yeast TDP-43 proteinopathy model: Exploring the molecular determinants of TDP-43 aggregation and cellular toxicity. Proc. Natl. Acad. Sci. USA 17:6439-6444. Gitler, A.D. (2008) Beer and bread to brains and beyond: Can yeast cells teach us about neurodegenerative disease? NeuroSignals 16:52–62. Cooper, A.A.*, A.D. Gitler*, A. Cashikar, C. Haynes, K. Hill, B. Bhullar, K. Liu, K. Xu, K.E. Strathearn, F. Liu, S. Cao, K.A. Caldwell, G.A. Caldwell, G. Marsischky, J. LaBaer, R.D. Kolodner, J.C. Rochet, N.M. Bonini, and S. Lindquist (2006) α-Synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 313:324-328. *These authors contributed equally |
