J. Timothy Greenamyre, MD, PhD

  • Professor, Neurology

Phone

412-648-9793

E-mail

jgreena@pitt.edu

Personal Website

website link

Education & Training

MD, University of Michigan Medical School (1986)
PhD, Unversity of Michigan (1986)

Location

Biomedical Science Tower 3, Room 7039

Research Interest Summary

Mechanisms of neurodegeneration and neuroprotection in Parkinson's and Huntington's diseases.

Currently, treatments for neurodegenerative diseases are inadequate; they typically address symptoms rather than the underlying degenerative process. As a result, we have no way to alter the inexorable progression of these devastating illnesses. My lab is interested in defining mechanisms of neurodegeneration in order to identify new targets for development of neuroprotective (Өdisease-modifyingӮ) therapeutic strategies. Most of our current work is on ParkinsonӮs disease (PD), and we are particularly interested in mitochondrial abnormalities and their roles in causing oxidative damage, protein aggregation and neurodegeneration.

About 90% of PD cases do not have a clear genetic cause and are therefore called ”®sporadic”Æ or ”®idiopathic”Æ cases. However, a large number of genetic mutations have been identified which can result in relatively rare inherited forms of the disease ØC and there are still other mutations which may not cause the disease, but greatly increase the risk of developing PD. Identification of such mutations has provided crucial clues about potential mechanisms that we are currently pursuing. We are particularly interested in the biological interactions between environmental exposures and genetic factors that increase disease risk.

Among other approaches, we are examining the potential benefits of Өgene therapyӮ approaches. Autosomal dominant mutations are generally thought to produce a detrimental Өgain-of-functionӮ for the affected protein, so the general approach is to reduce expression of those harmful proteins. On the other hand, autosomal recessive mutations are associated with a loss of function, so in this instance, we attempt to increase expression of the wildtype (normal) protein.

We are also working to develop ӨbiomarkersӮ of PD, using blood samples, that will help us determine whether neuroprotective, disease-modifying therapies are doing what they are designed to do.

The lab uses a wide range of techniques that include molecular biology, protein chemistry, immunocytochemistry, cell culture, live-cell imaging, behavioral testing and stereotactic surgery. Some work involves human tissue specimens.

Previous trainees have obtained tenured faculty positions, as well as jobs in Pharma and in disease-related foundations, such as the Michael J Fox Foundation. 

In Memoriam: Samay Jain.

Newman AB, Greenamyre JT.
J Am Geriatr Soc. 2017 Feb;65(2):446. doi: 10.1111/jgs.14715. No abstract available.
PMID: 28008600
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Pallanck, L., Greenamyre, J.T. Neurodegenerative disease: pink, parkin and the brain. Nature. 441(7097): 1058, 2006.

Berman, S.B., Greenamyre, J.T. Update on Huntington's disease. Curr Neurol Neurosci Rep. 6(4): 281-6, 2006.

Richardson, J.R., Caudle, W.M., Guillot, T.S., Watson, J.L., Nakamaru-Ogiso, E., Seo, B.B., Sherer, T.B., Greenamyre, J.T., Yagi, T., Matsuno-Yagi, A. and Miller, G.W. Obligatory role for complex I inhibition in the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Toxicol Sci. 95(1): 196-204,2007. Epub 2006 Oct 12.

Sherer, T.B., Richardson, J.R., Testa, C.M., Seo, B.B., Panov, A.V., Yagi, T., Matsuno-Yagi, A., Miller, G.W. and Greenamyre, J.T. Mechanism of toxicity of pesticides acting at complex I: relevance to environmental etiologies of Parkinson's disease. J Neurochem. 100(6):1469-79, 2007. Epub 2007 Jan 4.

Greenamyre, J.T. Huntington's disease--making connections. N Engl J Med. 356(5): 518-20, 2007.

Rocha EM, De Miranda BR, Castro S, Drolet R, Keeney M, Di Maio R, Kofler J, Hastings TG, Greenamyre JT, LRRK2 inhibition prevents endolysosomal deficits seen in human ParkinsonӮs disease, Neurobiol Dis, in press, 2019.

De Miranda BR, Rocha EM, Bai Q, El Ayadi A, Hinkle D, Burton EA and Greenamyre, JT, Astrocyte-specific DJ-1 overexpression protects against rotenone-induced neurotoxicity in a rat model of Parkinson's disease, Neurobiol Dis, doi: 10.1016/j.nbd.2018.04.008.

Di Maio R, Hoffman EK, Rocha EM, Keeney MT, Sanders LH, De Miranda BR, Zharikov A, Van Laar A, Stepan A, Lanz TA, Kofler JK, Burton EA, Alessi DR, Hastings TG, Greenamyre JT, LRRK2 activation in idiopathic Parkinson disease, Sci Transl Med., 10, eaar5429 (2018) doi: 10.1126/scitranslmed.aar5429.

Howlett EH, Jensen N, Belmonte F, Zafar F, Hu X, Kluss J, Schعle B, Kaufman BA, Greenamyre JT and Sanders LH, LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase-dependent and inhibition restores mtDNA integrity in Parkinson”Æs disease, Human Mol Genet 26:4340-4351, 2017.

Di Maio R, Barrett PJ, Hoffman EK, Barrett CW, Zharikov A, Borah A, Hu X, McCoy J, Chu CT, Burton EA, Hastings TG, Greenamyre JT. ¦Į-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease. Sci Transl Med 2016;8:342ra78.

Zharikov A, Cannon JR, Tapias V, Bai Q, Horowitz M, Shah V, El Ayadi A, Hastings TG, Greenamyre JT, Burton EA, shRNA targeting ¦Į-synuclein prevents neurodegeneration in a Parkinson”Æs disease model, J Clin Invest 125:2721-35, 2015.

Sanders LH, Laganiere J, Cooper O, Mak S, Vu BJ, Huang YA; Paschon D, Vangipuram M; Sundararajan R, Urnov F, Langston JW, Gregory P, Zhang HS, Greenamyre JT*, Isacson O, Schule B, LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: Reversal by gene correction, Neurobiol Dis 62:381-6, 2014.

Betarbet R, Canet-Aviles RM, Sherer TB, Mastroberardino P-G, McLendon C, Kim J-H, Lund S, Na H-M, Taylor G, Bence NF, Kopito R, Seo BB, Yagi T, Yagi A, Klinefelter G, Cookson MR, Greenamyre JT, Intersecting pathways to neurodegeneration in Parkinson's disease: effects of the pesticide rotenone on DJ-1 and ¦Į-synuclein and the ubiquitin-proteasome system, Neurobiol Dis. 22:404-420, 2006.

AV Panov, C-A Gutekunst, BR Leavitt, MR Hayden, JR Burke, WJ Strittmatter, JT Greenamyre, Early mitochondrial calcium defects in HuntingtonӮs disease are a direct effect of polyglutamines, Nature Neuroscience 5:731-736, 2002.

Betarbet, R, Sherer, TB, MacKenzie, G, Garcia-Osuna, M, Panov, AV and Greenamyre, JT, Chronic systemic pesticide exposure reproduces features of ParkinsonӮs disease, Nature Neuroscience 3:1301-1306, 2000.