Maryka Quik PhD, Program Director, Neurodegenerative Diseases Program

Dr. Quik received her PhD in Biochemistry from McGill University in Montreal, Canada. After a Medical Research Council postdoctoral fellowship at Cambridge University in England, she joined the faculty in the Department of Pharmacology at McGill University. She continued research and teaching at McGill and subsequently became full professor in Pharmacology. She then joined the Parkinson's Institute as Professor and Senior Research Scientist, after which she moved to SRI International as Director of the Neurodegenerative Diseases Program. Dr. Quik has published more than 125 research articles and reviews.

Dr. Quik’s research focuses on the relationship between the nicotinic cholinergic system and the dopaminergic system in addiction and neurodegenerative disorders. Tobacco addiction is associated with major health problems worldwide. Therefore strategies to reduce or stop smoking are needed urgently. Her lab investigates the effects of nicotine, an important addictive component in tobacco. They are investigating the role of novel nicotinic receptor subtypes using electrophysiological, molecular biology and behavioral techniques. These studies represent a new direction for understanding the changes in the brain that may be responsible for addiction. Such knowledge may lead to more effective treatment strategies for smoking cessation, which are critical in view of the detrimental health-related affects associated with tobacco use.

Dr. Quik’s lab is also investigating the potential usefulness of nicotine and nicotinic receptor drugs for Parkinson’s disease. This neurological movement disorder is characterized by a loss of dopaminergic neurons in the nigrostriatal pathway. Accumulating studies now show that nicotine protects against nigrostriatal damage. The mechanisms responsible for nicotine’s protective effects against degeneration of dopamine neurons are currently being investigated. Work is also in progress, which shows that nicotine may be useful for treating movement problems associated with L-dopa therapy in Parkinson's disease as nicotine reduces L-dopa-induced abnormal involuntary movements in different parkinsonian animal models. Studies are currently underway to determine the optimal nicotine treatment regimen and nicotine’s mechanisms of action including the use of knockout mouse models.  

Overall, this work has the potential to lead to the development of improved therapeutic approaches for addiction and neurodegenerative disorders such as Parkinson’s disease.

Selected Publications
Huang LZ, Parameswaran N, Bordia T, Michael McIntosh J, Quik M (2009) Nicotine is neuroprotective when administered before but not after nigrostriatal damage in rats and monkeys. J Neurochem 109:826-837.

Perez XA, O'Leary KT, Parameswaran N, McIntosh JM, Quik M (2009) Prominent role of alpha3/alpha6beta2* nAChRs in regulating evoked dopamine release in primate putamen: effect of long-term nicotine treatment. Mol Pharmacol 75:938-946.

Quik M, Campos C, Parameswaran N, Langston JW, McIntosh JM, Yeluashvili M (2009a) Chronic Nicotine Treatment Increases nAChRs and Microglial Expression in Monkey Substantia Nigra After Nigrostriatal Damage. J Mol Neurosci.

Quik M, Huang LZ, Parameswaran N, Bordia T, Campos C, Perez XA (2009b) Multiple roles for nicotine in Parkinson's disease. Biochem Pharmacol 78:677-685.

Bordia T, Campos C, Huang L, Quik M (2008) Continuous and intermittent nicotine treatment reduces L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in a rat model of Parkinson's disease. J Pharmacol Exp Ther 327:239-247.

O'Leary K, Parameswaran N, McIntosh JM, Quik M (2008a) Cotinine selectively activates a subpopulation of alpha3/alpha6beta2 nicotinic receptors in monkey striatum. J Pharmacol Exp Ther 325:646-654.

O'Leary KT, Parameswaran N, Johnston LC, McIntosh JM, Di Monte DA, Quik M (2008b) Paraquat exposure reduces nicotinic receptor-evoked dopamine release in monkey striatum. J Pharmacol Exp Ther 327:124-129.

Olivera BM, Quik M, Vincler M, McIntosh JM (2008) Subtype-selective conopeptides targeted to nicotinic receptors: Concerted discovery and biomedical applications. Channels (Austin) 2.

Perez XA, Bordia T, McIntosh JM, Grady SR, Quik M (2008a) Long-term nicotine treatment differentially regulates striatal alpha6alpha4beta2* and alpha6(nonalpha4)beta2* nAChR expression and function. Mol Pharmacol 74:844-853.

Perez XA, Parameswaran N, Huang LZ, O'Leary KT, Quik M (2008b) Pre-synaptic dopaminergic compensation after moderate nigrostriatal damage in non-human primates. J Neurochem 105:1861-1872.

Quik M, O'Leary K, Tanner CM (2008) Nicotine and Parkinson's disease: implications for therapy. Mov Disord 23:1641-1652.

Quik M, O'Neill M, Perez XA (2007b) Nicotine neuroprotection against nigrostriatal damage: importance of the animal model. Trends Pharmacol Sci 28:229-235.

Riveles K, Huang LZ, Quik M (2008) Cigarette smoke, nicotine and cotinine protect against 6-hydroxydopamine-induced toxicity in SH-SY5Y cells. Neurotoxicology 29:421-427.

Bordia T, Grady SR, McIntosh JM, Quik M (2007) Nigrostriatal damage preferentially decreases a subpopulation of alpha6beta2* nAChRs in mouse, monkey, and Parkinson's disease striatum. Mol Pharmacol 72:52-61.

Cox H, Togasaki DM, Chen L, Langston JW, Di Monte DA, Quik M (2007) The selective kappa-opioid receptor agonist U50,488 reduces L-dopa-induced dyskinesias but worsens parkinsonism in MPTP-treated primates. Exp Neurol 205:101-107.

Khwaja M, McCormack A, McIntosh JM, Di Monte DA, Quik M (2007) Nicotine partially protects against paraquat-induced nigrostriatal damage in mice; link to alpha6beta2* nAChRs. J Neurochem 100:180-190.

Quik M, Bordia T, O'Leary K (2007a) Nicotinic receptors as CNS targets for Parkinson's disease. Biochem Pharmacol 74:1224-1234.

Quik M, Cox H, Parameswaran N, O'Leary K, Langston JW, Di Monte D (2007c) Nicotine reduces levodopa-induced dyskinesias in lesioned monkeys. Ann Neurol 62:588-596.

Amy Manning-Bog, PhD, Program Manager, Neurodegenerative Diseases Program

Dr. Manning-Bog earned her PhD in Molecular & Cell Biology and Biochemistry from the University of Missouri-Kansas City. After a post-doctoral fellowship in neuropharmacology at Wayne State University in Detroit, MI, and a second fellowship at the Parkinson’s Institute to investigate neurodegenerative mechanisms in Parkinson's disease, she joined Renovis, Inc., a biotechnology company, as a scientist. She investigated novel therapeutic targets for neurodegenerative disorders before returning to the Parkinson’s Institute as assistant professor. Dr. Manning-Bog then joined the Center for Health Sciences in the Policy Division at SRI International as a program manager of the Neurodegenerative Diseases Program. She has written more than 15 research publications.

Dr. Manning-Bog’s research program focuses on intersecting mechanisms of degenerative disorders of the central nervous system, including Parkinson’s disease (PD), Alzheimer’s disease (AD), PD-dementia, Gaucher disease, and amyotrophic lateral sclerosis. Certain mutations in the redox-sensitive protein DJ-1 are linked to autosomal recessive forms of parkinsonism; however, DJ-1 modifications are detected in sporadic forms of PD and AD as well as other neurodegenerative diseases presenting with cognitive impairment. Her laboratory develops new models of DJ-1 deficiency to evaluate whether DJ-1 or its related pathways contribute to the development of mixed tau/alpha-synuclein pathology and related cognitive behavioral deficits. Another example of a shared mechanism of degeneration is indicated by studies showing increased risk of PD in individuals carrying mutations for Gaucher disease. Her laboratory also focuses on the relationship between Gaucher disease and PD to determine whether similar mechanisms of toxicity, specifically involving alpha-synuclein-lipid interactions, underlie neuronal damage in both disorders. Another commonality among risk factors for neurodegenerative diseases is environmental influence, particularly gene-environment interactions. A third arm of her research studies involves the impact of environmental modifiers and aging on genetic disposition, including LRRK2-related vulnerability using transgenic models of altered human LRRK2 expression. Lastly, Dr. Manning-Bog’s laboratory evaluates pre-clinical efficacy and mechanism(s) of action for a variety of putative therapeutic compounds for neurodegenerative disease. Through the study of gene-environment interactions and shared mechanisms of toxicity/pathology comes a better understanding of potential therapeutic targets for debilitating neurodegenerative disorders.

SELECTED PUBLICATIONS

Manning-Bog AB, Schule B, Langston JW (2009) Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: a biological link between Gaucher disease and parkinsonism. Neurotoxicology 30:1127-1132.

Manning-Bog AB, Caudle WM, Perez XA, Reaney SH, Paletzki R, Isla MZ, Chou VP, McCormack AL, Miller GW, Langston JW, Gerfen CR, Dimonte DA (2007) Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter. Neurobiol Dis 27:141-150.

Manning-Bog AB, Langston JW (2007) Model fusion, the next phase in developing animal models for Parkinson's disease. Neurotox Res 11:219-240.

Manning-Bog AB, Reaney SH, Chou VP, Johnston LC, McCormack AL, Johnston J, Langston JW, Di Monte DA (2006) Lack of nigrostriatal pathology in a rat model of proteasome inhibition. Ann Neurol 60:256-260.

Li J, Zhu M, Manning-Bog AB, Di Monte DA, Fink AL (2004) Dopamine and L-dopa disaggregate amyloid fibrils: implications for Parkinson's and Alzheimer's disease. Faseb J 18:962-964.

Goers J, Manning-Bog AB, McCormack AL, Millett IS, Doniach S, Di Monte DA, Uversky VN, Fink AL (2003) Nuclear localization of alpha-synuclein and its interaction with histones. Biochemistry 42:8465-8471.

Manning-Bog AB, McCormack AL, Purisai MG, Bolin LM, Di Monte DA (2003) Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci 23:3095-3099.

Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem 277:1641-1644.

McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, Di Monte DA (2002) Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 10:119-127.

Bannon MJ, Pruetz B, Manning-Bog AB, Whitty CJ, Michelhaugh SK, Sacchetti P, Granneman JG, Mash DC, Schmidt CJ (2002) Decreased expression of the transcription factor NURR1 in dopamine neurons of cocaine abusers. Proc Natl Acad Sci U S A 99:6382-6385.

Donato A. Di Monte, M.D., Senior Research Physician, Neurodegenerative Diseases Program

Dr. Di Monte received his Doctorate of Medicine and his Specialty training in Internal Medicine from the University of Bari, Italy. He completed post-doctoral research training in Biochemistry and Toxicology at the Karolinska Institute in Stockholm, Sweden, and at the School of Public Health, University of California, Berkeley.

Dr. Di Monte then joined the Parkinson’s Institute (Sunnyvale, California) as an independent investigator and developed a successful line of research sponsored by the NIH and other governmental and private agencies. He became Director of the Basic Research Department in 1997 and contributed to the Institute’s scientific growth and overall research accomplishments.

He moved to SRI International in 2009 with the intent of developing further his translational work on mechanisms of neurodegeneration and new therapeutics for Parkinson’s disease. Dr. Di Monte has served as a member of numerous study sections, project steering committees and scientific advisory boards. He has authored or co-authored more than 140 peer-reviewed scientific publications.

Specific areas of Dr. Di Monte’s current research interest include:

• Mechanisms of alpha-synuclein pathology. alpha-Synuclein is a protein involved in pathogenetic processes in Parkinson’s disease and other human neurodegenerative disorders. Its toxicity, as investigated by Dr. Di Monte’s research team, may arise from or be enhanced by abnormal aggregation, toxicant-protein interactions and an impairment of degradation.
• Environmental toxicants and aging as neurodegenerative disease risk factors. Aging is an unequivocal risk factor for human neurodegenerative diseases, and toxic exposures are likely to play an important role in the pathogenesis of Parkinson’s disease. Mechanisms by which these risk factors enhance neuronal vulnerability to degenerative processes include oxidative stress, neuroinflammation and alpha-synuclein abnormalities.  
• Screening and evaluation of neuroprotective/neurorestorative agents. No disease-modifying intervention is currently available for Parkinson’s disease. New therapeutic strategies that are currently being tested include the inhibition of alpha-synuclein expression using RNA interference-based technology.
• Pre-clinical evaluation of anti-dyskinetic drugs. Dyskinesias are involuntary movements that arise from the symptomatic treatment of Parkinson’s disease patients with L-dopa. They can be very debilitating and often interfere with patients’ quality of life as much as the disease itself. The evaluation of anti-dyskinetic agents, such as nicotine, at SRI is carried out in collaboration with Dr. Maryka Quik.
• Development and validation of new experimental models of Parkinson’s disease. Over the past years, Dr. Di Monte’s research has contributed to characterizing Parkinson’s disease features that can be reproduced by administration of toxicants (e.g. MPTP or paraquat) or transgenic overexpression of specific proteins (e.g., a-synuclein). The development of new experimental models provides critical tools for further investigating mechanisms of neurodegeneration and testing new therapeutics.

Selected Publications
Zhou W, Long C, Reaney SH, Di Monte DA, Fink AL, Uversky VN (2010) Methionine oxidation stabilizes non-toxic oligomers of alpha-synuclein through strengthening the auto-inhibitory intra-molecular long-range interactions. Biochim Biophys Acta 1802:322-330.

Mak SK, McCormack AL, Langston JW, Kordower JH, Di Monte DA (2009) Decreased alpha-synuclein expression in the aging mouse substantia nigra. Exp Neurol 220:359-365.

McCormack AL, Mak SK, Shenasa M, Langston WJ, Forno LS, Di Monte DA (2008) Pathological modifications of alpha-synuclein in MPTP-treated squirrel monkeys. J Neuropath Exp Neurol 67:793-802.

Fei Q, McCormack AL, Di Monte DA, Ethell DW (2008) Paraquat neurotoxicity is mediated by a Bak-dependent mechanism. J Biol Chem 283:3357-3364.

Quik M, Cox H, Parameswaran N, O’Leary K, Langston JW, Di Monte DA (2007) Nicotine reduces levodopa-induced dyskinesias in lesioned monkeys. Ann Neurol 62:599-596.

Caudle WM, Richardson JR, Wang MZ, Taylor TN, Guillot TS, McCormack AL, Colebrooke RE, Di Monte DA, Emson PC, Miller GW (2007) Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration. J Neurosci 27:8138-8148.

Purisai MG, McCormack AL, Cumine S, Li J, Isla MZ, Di Monte DA (2007) Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration. Neurobiol Dis 25:392-400.

Qin Z, Hu D, Han S, Reaney SH, Di Monte DA, Fink AL (2007) Effect of 4-hydroxy-2-nonenal modification on alpha-synuclein aggregation. J Biol Chem 282:5862-5870.

Quik M, Parameswaran N, McCallum SE, Bordia T, Bao S, Mc Cormack A, Kim A, Tyndale RF, Langston JW, Di Monte DA (2006) Chronic oral nicotine treatment protects against striatal degeneration in MPTP-treated primates. J Neurochem 98:1866-1875.

Manning-Bog AB, Reaney SH, Chou VP, Johnston LC, McCormack AL, Johnston J, Langston JW, Di Monte DA (2006) Lack of nigrostriatal pathology in a rat model of proteasome inhibition. Ann Neurol 60:256-260.

McCormack AL, Atienza JG, Langston JW, Di Monte DA (2006) Decreased susceptibility to oxidative stress underlies the resistance of specific dopaminergic cell populations to paraquat-induced degeneration. Neuroscience 141:929-937.

Purisai MG, McCormack AL, Langston WJ, Johnston LC, Di Monte DA (2005) alpha-Synuclein expression in the substantia nigra of MPTP-lesioned non-human primates. Neurobiol Dis 20:898-906.

McCormack AL, Atienza JG, Johnston LC, Andersen JK, Vu S, Di Monte DA (2005) Role of oxidative stress in paraquat-induced dopaminergic cell degeneration. J Neurochem 93:1030-1037.           

McCormack AL, Di Monte DA, Delfani K, Irwin I, DeLanney LE, Langston WJ, Janson AM (2004) Aging of the nigrostriatal system in the squirrel monkey. J Comp Neurol 471:387-395.

Manning-Bog AB, McCormack AL, Purisai MG, Bolin LM, Di Monte DA (2003) alpha-Synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci 23:3095-3099.

McCormack AL, Di Monte DA (2003) Effects of L-dopa and other amino acids against paraquat-induced nigrostriatal degeneration. J Neurochem 85:82-86.

McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, Di Monte DA (2002) Environmental risk factors and Parkinson’s disease: Selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 10:119-127.   

Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice. J Biol Chem 277:1641-1644.

Tanuja Bordia
Dr. Bordia received a PhD in Toxicology from the University of Rajasthan, India. She next did postdoctoral studies at the Parkinson’s Institute, and was subsequently promoted to Staff Scientist.

She then moved to SRI International with Dr. Quik, where she holds a position as Research Neuroscientist.

She is working on several projects researching nicotine-mediated effects in different Parkinson’s disease model and L-dopa-induced dyskinesias with particular emphasis on changes in nicotinic receptors. Dr. Bordia has authored or co-authored more than 19 scientific manuscripts.

Luping Huang

Dr. Huang received her MD at the Medical School of Shanghai Jiaotong University, China in 1999, and subsequently completed a two-year residency at Shanghai First People’s Hospital, China. Dr. Huang next obtained her PhD degree at Texas A&M University, College Station in 2006, after which she did postdoctoral training at the Parkinson’s Institute. Dr. Huang is currently a Research Neuroscientist in the Quik laboratory at SRI International.

Her research is focused on investigating the role of nicotinic receptor subtypes in L-dopa-induced dyskinesias using nicotinic receptor knockout mice. Dr. Huang has authored or co-authored more than 13 papers on Parkinson’s diseases and/or in nicotine-related research.

Alison McCormack
Dr. McCormack has a BSc from Thames Valley University and received a PhD in Neuroscience from the Karolinska Institute. This was followed by a post-doctoral fellowship at the Parkinson’s Institute. Dr. McCormack next moved to SRI International as a Research Neuroscientist with Dr. D. Di Monte.

Her research focuses primarily on how aging, genetic and environmental factors interact to influence the development of alpha-synuclein pathology in Parkinson’s disease. Dr. McCormack has authored or co-authored more than 35 scientific papers.

Xiomara Perez
Dr. Perez received a BS in chemistry from Temple University in 1999 and completed her PhD in analytical chemistry from the Pennsylvania State University in 2004. She then started her post-doctoral training at the Parkinson’s Institute under the supervision of Dr. Maryka Quik where she later became a staff scientist. Dr. Perez next moved to SRI International as a Research Neuroscientist with Dr. Quik.

Her research concentrates on investigating the effects of dopamine cell loss and chronic nicotine treatment on the dynamics of striatal dopamine neurotransmission, with a main focus on the role of nicotinic receptors in the control of dopamine release. Dr Perez has authored or co-authored more than 11 scientific papers.