Quyen Q. Hoang, Ph.D.
Assistant Professor, Department of Biochemistry and Molecular Biology
1993-1997 B.Sc. McMaster University, Hamilton, Canada
1997-2003 Ph.D. McMaster University, Hamilton, Canada
2004-2009 Postdoctoral Fellow, Rosensteil Basic Medical Sciences Research Center at Brandeis University, Waltham, Massachusetts, USA
Molecular Mechanisms of Neurodegeneration.
1) Structure and function of α-Synuclein (aSyn). Aggregation of aSyn leading to formation of Lewy bodies is a pathophysiological hallmark of PD. The function of aSyn and how it forms Lewy bodies was unclear, but the prevailing model was that aSyn is a natively unfolded protein. As such, it could easily misfold into aggregation prone species that then goes on to aggregate into Lewy bodies. However, in our effort to prepare samples suitable for determining the structure of aSyn using X-ray crystallography, we found that aSyn is in fact not natively unfolded, but instead it forms a stably folded tetramer. We are now focusing on determining the crystal structure of aSyn to understand the structural bases for Lewy body formation.
2) Role of inflammation in the pathogenesis of Parkinson’s disease. We recently found that activating the inflammation pathways with various chemical agents led to proteolytic cleavage of aSyn and rendering it aggregation prone in vitro and in vivo. We are now investigating the molecular consequences of aSyn under these inflamed conditions in neurons to better understanding the toxic species and disease pathways. We are also testing whether inhibiting inflammation could be an effective therapeutic strategy.
3) Stabilization of aSyn as a potential therapeutic strategy. The above discoveries led us to create a new model of aSyn aggregation, in which we hypothesize that aSyn normally exists as a folded tetramer. Disease occurs when the tetramer is destabilized and rendered aggregation prone by mutations or post-translational modifications. We are using this model to help develop novel therapeutics by designing compounds that could stabilize the tetramer form of aSyn. We, in collaboration with Dr. Hyun-Suk Lim’s group, recently developed 2 such compounds that bind tightly to aSyn (nanomolar range) and effectively inhibited aSyn aggregation. We are now attempting to improve the pharmacokinetics of these compounds and testing their efficacy in cell models of Parkinson’s disease.
4) Structure and function of LRRK2. Mutation in Leucine Rich Repeat Kinase 2 (LRRK2) is a common cause of PD. LRRK2 is a large multi-domain protein whose function is unknown. It is an attractive drug target because it consists of enzymatic domains, which consist of pockets into which we can fit drug molecules – because of that virtually every major drug company has a LRRK2 project. However, the mechanism of LRRK2 in disease pathogenesis is completely unknown. A prevailing model was that LRRK2 dimerizes via its GTPase domain (Roc) or via a domain C-terminal of Roc (Cor) and that this dimerization is necessary for its GTPase activity. However, we found that Roc in its monomeric form is equally active compared to the dimeric form. We further determined that a disease-associated mutation R1441H pathologically locks the Roc domain in a persistently active state.
We are now focusing on understanding the mechanism of R1441H in modulating Roc activity by determining its atomic structures using X-ray crystallography. We will use this information to develop compounds that could reverse the effects caused by disease-associated mutations, which we hope would further develop into effective drugs to combat this devastating disease.
Selected Recent Publications:
1. Hoang QQ, Sicheri F, Howard AJ, Yang DSC. Bone recognition mechanism of porcine osteocalcin from crystal structure. Nature. 425: 977-980 (2003)
2. Das C*, Hoang QQ*, Kreinbring CA, Luchansky SJ, Meray RK, Ray SS, Lansbury PT, Ringe D, Petsko GA. Structural Basis for Conformational Plasticity of the Parkinson's Disease-Associated Ubiquitin Hydrolase UCH-L1. Proc Natl Acad Sci U S A. 103(12): 4675-80 (2006) (* Co-first author)
3. Pau VP, Zhu Y, Yuchi Z, Hoang QQ, Yang DS. Characterization of the C-terminal domain of a potassium channel from Streptomyces lividans (KcsA) J Biol Chem. 282(40): 29163-9 (2007)
4. Liu D, Thomas PW, Momb J, Hoang QQ, Petsko GA, Ringe D, Fast W. Structure and specificity of a quorum-quenching lactonase (AiiB) from Agrobacterium tumefaciens. Biochemistry. 46(42): 11789-99 (2007)
5. Ataie N, Hoang QQ, Dybig M, Milne A, Petsko GA and Ringe D. Zinc Coordination Geometry and Ligand Binding Affinity: The Structual and Kinetics Analysis of the Second-Shell Serine 228 Residue and the Methionine 180 Residue of the Aminopeptidase from Vibrio proteolyticus. Biochemistry. 47(29): 7673-83 (2008)
6. Landon MR, Lieberman RL, Hoang QQ, Ju S, Caaveiro JMM, Orwig SD, Kozakov D, Brenke R, Chuang GY, Beglov D, Vajda S, Petsko GA, Dagmar Ringe D. Detection of ligand binding hot spots on protein surfaces via fragment-based methods: Application to DJ-1 and Glucocerebrosidase. J. Comput Aided Mol Des. 23:491-500 (2009)
7. Wang W, Perovic I, Chittuluru J, Kagnanovich A, Nguyen LTT, Liao J, Auclair JR, Johnson D, Landeru A, Simorellis AK, Ju S, Cookson M, Asturias FJ, Agar JN, Webb BN, Kang CH, Ringe D, Gregory Petsko GA, Pochapsky TC, and Hoang QQ. A soluble alpha-Synuclein construct forms an ordered tetramer. Proc Natl Acad Sci U S A. 108(43): 17797-802 (2011)
8. Zhang Q, Xiao H, Chai SC, Hoang QQ, Lu H. Hydrophilic residues are crucial for RPL11 interaction with the zinc finger domain of mdm2 and P53 activation. J Biol Chem. 286(44): 38264-74 (2011)
9. Wu R, Edayathumangalam R, Wang Y, Garcia R, Wang W, Kreinbring S, Liao J, Stone T, Hoang QQ, Boris Belitsky, Gregory A Petsko, Ringe D, Dali Liu. Crystal structure of Bacillius subtilis GabR, an autorepressor and transcription activator of gabT. Proc Natl Acad Sci U S A. 110(44): 17820-5 (2013)
10. Liao J, Wu C, Burlak C, Zhang S, Sahm H, Wang M, Zhang ZY, Vogel KW, Federici M, Riddle SM, Nichols RJ, Liu D, Cookson MR, Stone TA, Hoang QQ. The Parkinson’s disease-associated mutation R1441H in LRRK2 prolongs the ‘active-state’ of its GTPase domain. Proc Natl Acad Sci U S A. 111(11): 4055-60 (2014)
11. Hoang QQ. Pathway for Parkinson’s disease. Proc Natl Acad Sci U S A. 111(17): 2402-3 (2014)
12. Tashiro A, Caaveiro JM, Wu CX, Hoang QQ, Tsumoto K. Thermodynamic and structural characterization of the specific binding of Zn(II) to Human DJ-1. Biochemistry. 53(14): 2218-20 (2014)
13. Oh M, Lee JH, Wang W, Lee HS, Lee WS, Burlak C, Im W, Hoang QQ*, and Hyun-Suk Lim*. Pharmacological Chaperones Targeting Cancer-Associated MCL-1 and Parkinson’s Disease-Associated α-Synuclein. Proc Natl Acad Sci U S A. 1111(30):11007-12 (2014) (* corresponding authors)