Department / Division Affiliations
|Professor, Molecular & Medical Pharmacology|
|Member, Brain Research Institute|
My lab investigates molecular genetic mechanisms underlying the two most common neurodegenerative disorders, Alzheimer's disease (AD) and Parkinson's disease (PD), which affect half of the population over the age of 80. We aim to understand the disease mechanisms and to translate the findings into human studies. One key pathological hallmark 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, the Amyloid Precursor Protein (APP), through the action of two proteases, one of which is gamma-secretase with Presenilins being the catalytic core. Both high levels of APP, and aberrant cleavage of APP by mutations in APP, Presenilin 1 and Presenilin 2, lead to familial forms of AD. We have developed an in vivo reporter system to identify regulators of APP levels and gamma-secretase activities through function-based, genome-wide genetic screens. We have identified multiple enhancers and suppressors of this in vivo reporter, and are in the process of characterizing the functions of these genes. These finding are likely to provide new diagnostic tools and/or therapeutic targets. Mutations in PINK1 and PARKIN result in autosomal recessive forms of PD. We are among the first worldwide to report the function of PINK1, and to discover that PINK1 and PARKIN act in a common genetic pathway to regulate mitochondrial integrity and mitochondrial quality control. This is accomplished, at least in part, through regulation of the mitochondrial fusion and fission dynamics. Recently, we have identified a new gene known as MUL1 that, when overexpressed, suppresses PINK1/parkin mutant-related defects in mitochondrial integrity and tissue damage. When deleted, MUL1 exacerbates defects due to lack or PINK1 or parkin. MUL1 acts in parallel pathways to PINK1/parkin to degrade the pro-mitochondrial fusion protein Mitofusin. Increased levels of Mitofusin are sufficient to cause cell death and mitochondrial damage. Thus, optimizing MUL1 levels is critically important, and both MUL1 and Mitofusin are promising therapeutic targets. In addition to PD, our work also has wide-ranged implications for controlling processes in aging, and other aging-related diseases including other neurodegenerative disorders, heart disease and metabolic disorders.
Zhang T, Mishra P, Hay BA, Chan D and Guo M VCP inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants. eLife 2017; in press: .
Kandul, N.P., Zhang, T., Hay, B.A.*, and Guo, M* (equal contribution). Selective removal of deletion-bearing mitochondrial DNA in heteroplastic Drosophila. Nature Communications 2016; in press: .
Harteinstein, V.*, Cruz, L., Lovick, J.K., and Guo, M.* (co-correspondence) Developmental analysis of the dopamine-containing neurons of the Drosophila brain. Journal of Comparative Neurology 2016; .
Yun, J., Puri, R.*, Yang, H.*, Lizzio, M., Wu, C., Sheng, Z.H. and Guo, M. MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin. eLife 2014; 3(e01958): (equal contribution).
Dauer WT, Guo M. Multiplying messages LRRK beneath Parkinson disease. Cell 2014; 157: 291-293.
Dodson, M.W., Leung, L.K., Lone, M. Lizzio, M.A. and Guo, M. Novel alleles of the Drosophila LRRK2 homolog reveal a crucial role in endolysosomal functions and autophagy in vivo. Disease Models and Mechanisms 2014; 7:: 1351-63.
Gross GG, Lone GM, Leung LK, Hartenstein V, Guo M. X11/Mint genes control polarized localization of axonal membrane proteins in vivo. J. Neurosci. 2013; 33: 8575-8586 (cover story).
Guo, M. Drosophila as a model to study mitochondrial dysfunction in Parkinson's disease. Cold Spring Harb. Perspect. Med 2012; a009944: .
M.W. Dodson, T. Zhang, C. Jiang, S. Chen and M. Guo Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning. Human Molecular Genetics 2012; 21: 1350-1363.
J.C. Rochet, B.A. Hay and M. Guo Molecular Insights into Parkinson's Disease. Progress in Molecular Biology and Translational Science 2012; 107: 125-188.
M. Guo What have we learned from Drosophila models of Parkinson?s disease. Progress in Brain Research 2010; 184: 3-17.
B.A. Hay, C.H. Chen, C. M. Ward, H. Huang. J. T.Su, and M. Guo Engineering the genomes of wild insect populations: Challenges, and opportunities provided by synthetic Medea selfish genetic elements. J. Insect Physiol. 2010; 56: 1402-1413.
Li, H. and Guo, M. Protein Degradation in Parkinson Disease Revisited: It's Complex . J. Clinical Invest 2009; 119: 442-445.
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.
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.
Gross, G.G. Feldman, R. Ganguly, A. Wang, J. Yu, H. and Guo, M. Role of X11 and ubiquilin as in vivo regulators of the amyloid precursor protein in Drosophila. PLoS ONE. 2008; 3: e2495.
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.
Hay, B.A. and Guo, M. Caspase-Dependent Cell Death in Drosophila. Annu. Rev. Cell Dev. Biol. 2006; 22: 623-650.
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.
Xu P, Guo M, Hay BA. MicroRNAs and the regulation of cell death. Trends Genet 2004; 20(12): 617-624.
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., Hay, B. Cell proliferation and apoptosis. Curr Opin Cell Biol. 1999; 11: 745-752.
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.