Donato A. Di Monte

Donato Di Monte, M.D., is a senior research physician in the Neurodegenerative Diseases Program in SRI International’s Center for Health Sciences. He 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.

Di Monte then joined the Parkinson’s Institute in Sunnyvale, California as an independent investigator. There, he developed a successful line of research sponsored by the National Institutes of Health 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 in 2009 with the intent of developing further his translational work on mechanisms of neurodegeneration and new therapeutics for Parkinson’s disease.

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 current research areas of 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 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 Maryka Quik, Ph.D.

• Development and validation of new experimental models of Parkinson’s disease. Over the past years, 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.