Laboratory Address:
Laboratory Gonda 3309 UNITED STATES
Work Address:
Office Gonda 3309A UNITED STATES
Work Phone Number:
310-206-9406
310-794-4851
|
| ACCESS Affinity - Molecular Basis of Disease |
|
We are interested in understanding mechanisms underlying neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD) using Drosophila as a model system. AD and PD are the two most common neurodegenerative disorders, affecting half of the population over the age of 85. We aim to understand the molecular mechanisms leading to these two diseases in Drosophila and to translate the findings into human studies in the future. One of the pathological hallmarks of AD is the accumulation of amyloid plaques consisting of a toxic peptide known as A-beta. A-beta is generated from a transmembrane protein, Amyloid Precursor Protein (APP), through the action of two proteases, one of which is gamma secretase. Gamma secretase is contained in a large multi-protein complex including Presenilin. We have developed an in vivo reporter system to identify regulators of gamma secretase through function-based genetic screen in the eye (HMG 12:2669, 2003). We have identified multiple enhancers and suppressors of gamma-secretase activity via genetic screens, and are in the process of characterizing the functions of these modifiers. The identification of regulators for the gamma secretase complex is likely to provide new diagnostic tools and/or therapeutic targets. Recently, five genes definitively linked to familial PD have been identified. We have shown that flies lacking one of these, pink1, which encodes a mitochondria localized kinase, result in defects in mitochondrial morphology and function, increased sensitivity to stress and reduced life span. In addition, pink1 acts in the same genetic pathway as parkin, another gene linked to familial PD that encodes an E3 ubiquitin ligase (Nature, in press). The identification of a pink1/parkin pathway underscores the importance of mitochondrial dysfunction as a central mechanism for PD pathogenesis. Using Drosophila genetics, we are in a unique position to identify new components of this pathway and to dissect the molecular mechanisms that lead to mitochondrial dysfunction.
|
|
Ming Guo received her Ph.D. from Yuh Nung Jan's laboratory at the University of California, San Francisco for her work on how NUMB regulates NOTCH during asymmetric divisions in Drosophila neuronal stem cell development. After her residency training in Neurology at UCLA and a short postdoc in Larry Zipursky's laboratory, she became an assistant professor in neurology at the UCLA School of Medicine. She is an Alfred P. Sloan Foundation fellow, Larry Hillblom Foundation Startup Grantee, Ellison Medical Foundation New Scholar in Aging, McKnight Neuroscience Foundation Brain Disorder Awardee and Klingenstein Fellow. She also cares for patients with neurological disorders at the UCLA Medical Center and is a national Board Examiner for American Board of Psychiatry and Neurology. The Guo laboratory works on mechanisms of neurodegerative diseases using D. melanogaster as a model. Much of the focus is on studying molecular mechanisms of the two most common neurodegenerative disorders, Alzheimer disease and Parkinson's disease.
|
Yun, J.
Cao, J.H.
Dodson, M.W
Clark, I.E.
Kapahi, P.
Chowdhury, R.B.
and Guo, M. Loss-of-function analysis suggests that Omi/HtrA2 is not an essential component of the pink1/parkin pathway in vivo.
J. Neurosci..
2008; 28:
14500-14510.
Deng, H.
Dodson, M.W.
Huang, H.
Guo, M. The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or fusion in Drosophila..
PNAS.
2008; 105:
14503-14508.
Ganguly, A.*, Feldman, R.* and Guo, M. ubiquilin antagonizes presenilin and promotes neurodegeneration..
Human Molecular Genetics.
2008; 17:
293-302. (Cover Story).
Chen, C., Huang, H., Ward, C., Su, J., Schaeffer, L., M. Guo and Hay, B.A. A Synthetic Maternal-Effect Selfish Genetic Element Drives Population Replacement in Drosophila .
Science.
2007; 316:
597-600.
Dodson, M.W. and Guo, M. Pink1, Parkin, DJ-1 and Mitochondrial Dysfunction in Parkinson's Disease.
Curr. Opin. Neurobiol..
2007; 17:
331-337.
Clark, I.E*., Dodson, M.W.*, Jiang, C.*, Cao, J.H., Huh, J.R., Seol, J.H., Yoo, S.J., Hay, B.A. and Guo, M.
Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin .
Nature.
2006; 441:
1162-1166.
Xu P, Guo M, Hay BA. MicroRNAs and the regulation of cell death..
Trends Genet.
2004; 20(12):
617-624.
Guo, M., Hay, B. Cell proliferation and apoptosis..
Curr Opin Cell Biol.
1999; 11:
745-752.
Hay, BA, Huh, JR and Guo, M The genetics of cell death: approaches, insights and opportunities in Drosophila..
Nature Review Genetics .
2004; 5(12):
911-22.
Guo, M Hong, EJ Fernandes, J Zipursky, SL Hay, BA A reporter for amyloid precursor protein gamma-secretase activity in Drosophila..
Human molecular genetics. .
2003; 12(20):
2669-78.
Hay, BA Guo, M Coupling cell growth, proliferation, and death. Hippo weighs in..
Developmental cell. .
2003; 5(3):
361-3.
Xu, P Vernooy, SY Guo, M Hay, BA The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism..
Current biology : .
2003; 13(9):
790-5.
Guo, M Jan, LY Jan, YN Control of daughter cell fates during asymmetric division: interaction of Numb and Notch..
Neuron. .
1996; 17(1):
27-41.
Guo, M Bier, E Jan, LY Jan, YN tramtrack acts downstream of numb to specify distinct daughter cell fates during asymmetric cell divisions in the Drosophila PNS..
Neuron. .
1995; 14(5):
913-25.
|
|
|
