Faculty Research : Faculty Research Detail

R. Grace Zhai, Ph.D.

Assistant Professor, Molecular and Cellular Pharmacology

305-243-6316 (office)

305-243-4555 (fax)

Rosenstiel Medical Science Building, Room 6069

gzhai@med.miami.edu

Curriculum Vitae

B.S., Biochemistry, Wuhan University, P. R. China 1989-1993

M.S., Neuropharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, P. R. China 1993-1996

Ph.D. Neurobiology, University of Alabama at Birmingham, 1996-2001

Postdoc, Molecular and Human Genetics, Baylor College of Medicine, 2001-2006

Assistant Professor, Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, January 2007-present

Research Interests

The research in my laboratory is directed toward understanding the genetic and cellular basis of neural development, degeneration and protection using the fruit fly Drosophila melanogaster as a model system.

Neurons are highly polarized cells with elaborate projections. At the terminal of each projection are highly specialized cell-cell contacts, or synapses, where neurotransmission occurs. Sending out numerous processes and making specific synaptic contacts with target cells are daunting tasks for each neuron. More importantly, all these processes and synapses have to be maintained to ensure the normal function of the brain. Healthy neurons are able to maintain their integrity throughout the lifespan, suggesting the existence of a maintenance mechanism that allows neurons to sustain or even repair damage. When such a maintenance system is damaged (owing to a genetic mutation for example), or there is a toxic insult at levels surpassing the maintenance capacity, neurons will deteriorate. Conversely, strengthening the maintenance system may serve to increase the capability of neurons to tolerate insults, from internal or external sources. Therefore, studying the mechanisms of neuronal maintenance will help us understand the process of neurodegeneration, and more importantly uncover potential mechanisms of neuronal protection.

The Drosophila model system

The central and peripheral nervous systems of Drosophila are remarkably similar to vertebrates functionally and morphologically. The specific advantages of the Drosophila model system for neurobiology include the following: First, Drosophila is an organism simple enough to allow large scale genetic screens to identify novel components in neuronal processes. Especially the recent development of genetic tools such as the FLP/FRT system allows the generation of mosaic flies where only a subset of neurons are rendered homozygous for the mutation, while the rest of tissues are heterozygous. These genetic tools make it possible to study the neuronal phenotypes of lethal mutations in the adult nervous system. Second, the nervous system of Drosophila is complex enough to resemble that of vertebrates in basic functions and morphology. Some fundamental mechanisms and key components of processes such as neurodevelopment, neural fate specification, and synaptic transmission are conserved between flies and vertebrates. Therefore, we could take advantage of the genetic capacity of the Drosophila model system to dissect complex neuronal mechanisms which will help us understand the functions of the vertebrate nervous system.

Project 1 Molecular Mechanisms of neurodegeneration

From the forward genetic screen designed to isolate mutations that cause neuronal malfunction in the adult brain, we have identified mutations in a gene called nmnat that cause a rapid and severe neurodegeneration immediately after the completion of neuronal differentiation and development. We further found that NMNAT protein is required to maintain neuronal integrity and this function can be exploited to protect neurons from degeneration under adverse conditions. Our discovery of such a neuronal ‘maintenance factor' reveals that neurons constantly protect themselves against toxic insults and a failure of this defense system for example due to a genetic mutation leads to neurodegeneration or neuronal death. Understanding the details of the defense mechanism will not only provide insights into the cellular process of neuronal maintenance, but also offers a unique angle to tackle the mechanisms of neurodegeneration.

Project 2 Mechanisms of synapse development and maintenance

The establishment of synapses is required for neuronal function. However, the molecular components of active zone structures in both mammalian and Drosophila synapses are largely unknown and how active zones are assembled and maintained are unclear. From a forward genetic screen, we have isolated mutants with specific defects in synapse formation including abnormal active zone structure, malfunction of the regulation of synapse assembly, and disruption of synapse maintenance. Currently, we are trying to identify the genetic causes of these mutations. The subsequent characterization of these genes will reveal the molecular constituents of the active zone and shed light on the mechanisms governing the assembly and maintenance of synapses.

Lab members

Zoraida Diaz-Perez: research associate and lab manager

Wilfredo Escala: undergraduate student

Brandon Kitay: graduate student (Neuroscience Program)

Omar Nelson: Postdoctoral Associate

Kai Ruan: graduate student (Pharmacology Program)

Shaoyun Zang: graduate student (Pharmacology Program)

Lab Alumni

Yousuf Ali: former graduate student (Pharmacology Program) currently a postdoc in Dr. Virginia Lee's lab at U Penn

Fan Zhang: former postdoc

Recent Publications

Ouyang, H, Ali YO, Ravichandran M, Dong A, Qiu W, MacKenzie F, Dhe-Paganon S, Arrowsmith CH, and Zhai RG. (2011) Protein aggregates are recruited to the aggresome by histone deacetylase 6 via unanchored ubiquitin c-termini. J. Biol. Chem. 2011 Nov 8. [Epub ahead of print] PMID: 22069321.

Ljungberg, MC, Ali YO, Zhu J, Oka K, Zhai RG, and Lu HC (2011) CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy. Hum Mol Genet. 2011 Oct 25. [Epub ahead of print] PMID: 22027994.

Ali, YO, Ruan K, and Zhai RG. (2011) NMNAT suppresses Tau-induced neurodegeneration by promoting clearance of hyperphosphorylated Tau oligomers in a Drosophila model of tauopathy. Hum Mol Genet. 2011 Oct 13. [Epub ahead of print] PMID: 21965302.

Wen, Y, Parrish JZ, Zhai RG, and Kim MD (2011) Nmnat is required for dendrite maintenance in Drosophila. Molecular Cellular Neuroscience 48(1):1-8. PubMed Central PMCID: PMC3152617

Ali, YO, McCormack R, Darr A, Zhai RG (2011) Nicotinamide mononucleotide adenylyltransferase (nmnat) is a stress response protein regulated by the hsf/hif1α pathway. J. Biol. Chem. 286(21):19089-99. PubMed Central PMCID: PMC3099722

Ali, YO, Escala W, Ruan K, and Zhai RG (2011) Assaying locomotor and learning and memory deficits in Drosophila models of neurodegeneration. J Vis Exp. 11(49) doi: 10.3791/2504. NIHMS304364 PubMed PMID: 21445036; PubMed Central PMCID: PMC3197301.

Zhou, X, Escala W, Papapetropoulos S, and Zhai RG (2010) β-N-methylamino-L-alanine induces neurological deficits and shortened life span in Drosophila. Toxins 2(11):2663-2679.

Ali YO, Kitay BM, and Zhai RG (2010) Dealing with misfolded proteins: examining the neuroprotective role of molecular chaperones in neurodegeneration. Molecules 15(10):6859-87. PubMed PMID: 20938400; PubMed Central PMCID: PMC3133442

Zhou, X, Escala W, Papapetropoulos S, Bradley WG, and Zhai RG (2009) BMAA neurotoxicity in Drosophila. Amyotrophic Lateral Sclerosis. 10 Suppl 2:61-6.

Zhai, RG, Rizzi M, and Garavaglia S (2009) Nicotinamide/Nicotinic Acid Mononucleotide Adenylyltransferase (NMNAT), new insights into an ancient enzyme. Cellular Molecular Life Sciences. 66(17):2805-18.

Zhai, RG*, Zhang F, Hiesinger PR, Cao Y, Haueter CM, and Bellen HJ (2008) NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. Nature 452(7189):887-91*corresponding author. Featured Highlight in Nature Reviews Neuroscience 9, 323. Wiedemann, C. Neurodegenerative disease: Understanding and preventing total catastrophe

Zhai, RG (2008) The architecture of the presynaptic release site. In Molecular Mechanisms of Neurotransmitter Release, ed. Wang ZW. The Humana Press Inc.

Zhai, RG, Cao Y, Hiesinger PR, Zhou Y, Mehta SQ, Schulze KL, Verstreken P, and Bellen HJ (2006) Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity. PLoS Biology 4(12): e416.

Hiesinger, PR*, Zhai, RG*, Zhou Y, Koh T-W, Mehta SQ, Verstreken P, Schulze KL, CaoY, Clandinin TR, Fischbach K-F, Meinertzhagen IA, and Bellen HJ (2006) Activity-independent pre-specification of synaptic partners in the visual map of Drosophila. Current Biology 16: 1835-1843. *co-first authors

Hiesinger, PR, Fayyazuddin A, Mehta SQ, Rosenmund T, Schulze KL, Zhai RG, Verstreken P, Cao Y, Zhou Y, Kunz J, and Bellen H J. (2005) The v-ATPase V0 subunit a1 is required for a late step in synaptic vesicle exocytosis in Drosophila. Cell 121(4):607-620.

Mehta SQ, Hiesinger PR, Beronja S, Zhai RG, Schulze KL, Verstreken P, Cao Y, Zhou Y, Tepass U, Crair MC, and Bellen HJ. (2005) Mutations in Drosophila sec15 reveal a function in neuronal targeting for a subset of exocyst components. Neuron 46(2): 219-32.

Zhai, RG, Bellen HJ. (2004) Hauling t-SNAREs on Microtubule Highway Nature Cell Biology 6:918-919.

Zhai, RG, Bellen HJ. (2004) The Architecture of the Active Zone in the Presynaptic Nerve Terminal.Physiology 19: 262-270.

Verstreken P, Koh TW, Schulze KL, Zhai RG, Hiesinger PR, Zhou Y, Mehta SQ, Cao Y, Roos J, Bellen HJ. (2003) Synaptojanin Is Recruited by Endophilin to Promote Synaptic Vesicle Uncoating. Neuron 40(4):733-748.

Zhai, RG, Hiesinger PR, Verstreken P, Koh T-W, Schulze K, Greenbaum M, Cao Y, Bellen BJ. (2003) Mapping of Drosophila mutations with molecularly mapped P-elements. Proc. Natl. Acad. Sci. U.S.A. 100(19):10860-5. Featured Highlight in Nature Reviews Genetics 4, 849.Casci, T. I can name it in three…

Shapira, M*, Zhai RG* , Dresbach T, Bresler T, Torres VI, Gundelfinger ED, Ziv NE and Garner CC. (2003) Unitary Assembly of Presynaptic Active Zones from Piccolo-Bassoon Transport Vesicles. Neuron 38(2): 237-252. * Co-first authors

Garner, CC, Zhai RG, Gundelfinger ED, Ziv NE. (2002) Molecular mechanisms of CNS synaptogenesis. Trends in Neuroscience 25(5): 243-51.

Zhai, RG, Vardinon-Friedman H, Cases-Langhoff C, Becker B, Gundelfinger ED, Ziv NE and Garner CC. (2001) Assembling the Presynaptic Active Zone, the Identification of an Active Zone Precursor Vesicle.Neuron 29(1): 131-143.

Bresler T, Ramati Y, Zamorano PL, Zhai R, Garner CC, Ziv NE. (2001) The dynamics of sap90/psd-95 recruitment to new synaptic junctions. Mol Cell Neurosci;18(2):149-167.

Fenster, SD*, Chung WJ*, Zhai R* Cases-Langhoff C, Voss B, Garner AM, Kampf U, Gundelfinger ED, and. Garner CC. (2000) Piccolo, a presynaptic zinc finger protein structurally related to Bassoon. Neuron 25(1): 203-214. * Co-first authors

Zhai, R, Olias G, Chung WJ, Lester RAJ, tom Dieck S, Langnaese K, Kreutz MR, Kindler S, Gundelfinger ED and Garner CC. (2000) Temporal appearance of the presynaptic cytomatrix protein Bassoon during synaptogenesis. Molecular Cellular Neuroscience, 15(5):417-28.

Richter, K., Langnaese K, Kreutz MR, Olias G, Zhai R, Scheich H, Garner CC, and Gundelfinger ED. (1999) Presynaptic cytomatrix protein Bassoon is localized at both excitatory and inhibitory synapses of rat brain. J. Comp. Neurol 408:437-448.

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