Greenamyre Laboratory

Tim Greenamyre, MD, PhD

Tim Greenamyre, MD, PhD

Love Family Professor & Vice-Chair of Neurology
Chief, Movement Disorders Division
Director, Pittsburgh Institute for Neurodegenerative Diseases
E-mail

Interests

Currently, treatments for neurodegenerative diseases are inadequate; they only 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 (‘disease-modifying’) therapeutic strategies. Most of our current work is on Parkinson’s 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’ or ‘idiopathic’ cases. However, a large number of genetic mutations have been identified which can result in relatively rare inherited forms of the disease – 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.

In collaboration with Dr. Ed Burton, we are examining the potential benefits of ‘gene therapy’ approaches. Autosomal dominant mutations are generally thought to produce a detrimental ‘gain-of-function’ 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, together with Dr. Laurie Sanders, to develop ‘biomarkers’ of PD, such as mtDNA damage, that will help us determine whether neuroprotective 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.

Training

BS Microbiology Michigan State University 1977
PhD Neuroscience University of Michigan 1986
MD Medicine University of Michigan 1986
Resident Neurology University of Michigan 1990

Positions Held

Assistant - Associate Professor University of Rochester 1990-1995
Associate - Full Professor Emory University 1995-2005
Professor & Director University of Pittsburgh 2005-

Honors and awards

Medical Scientist Award, University of Michigan Medical School (1986)
Best Doctors in America (1994)
Medical/Scientific Advisory Committee Huntington’s Disease Society of America (1994-2004)
Scientific Advisory Board, Dystonia Medical Research Foundation (1995-98)
Mallinckrodt Scholar (1994-97)
Chair, Grants & Fellowships Program, Huntington’s Disease Society of America (1998-2003)
Ottorino Rossi Award and Medal of the University of Pavia, Pavia, Italy (2000)
Scientific Advisory Board, Parkinson Study Group (2001-2008)
Scientific Advisory Committee, Michael J. Fox Foundation (2001-present)
Scientific Committee, Telethon-Italy (2002-05), Chair, Scientific Advisory Committee, Parkinson Study Group (2004-08)
Team Hope Award for Medical Leadership, Huntington’s Disease Society of America (2003)
Presidential Lecture, Annual Meeting of the SfN (2004)
Editor-in-Chief, Neurobiology of Disease (2004-present)
Executive Committee, Michael J. Fox Foundation (2005)
Chair, NINDS Special Emphasis Panel: ZNS1 SRB-G 04: ‘Cell biology of Parkinson’s disease’ (2005)
SFN Grass Traveling Lecturer, Omaha, NE (2005)
Langston Award, Michael J. Fox Foundation (2007)
Best Doctors in America (2007-present)
NOMD Study Section, NIH (2010-14; Chair, 2012-14)
Executive Committee, Michael J. Fox Foundation (2013-15)
Editor-in-Chief, MedLink Neurology (2013-present)
Elected, American Association of Physicians (2015)
Co-Chair, Gordon Research Conference on Parkinson’s disease (2015-17).

Gallery

Selected Publications

Schapira AH, Olanow CW, Greenamyre JT and Bezard E, Fighting neurodegeneration in Parkinson and Huntington diseases: Future therapeutic perspectives, The Lancet 384:545-55, 2014.

Sanders LH and Greenamyre JT, Oxidative damage to macromolecules in human Parkinson disease and the rotenone model, Free Rad Biol Med 62:111-120, 2013. PMC3677955

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. *corresponding author PMC3877733

Sanders LH, McCoy J, Hu X, Mastroberardino PG, Dickinson BC, Chang CJ, Chu CT, Van Houten B, Greenamyre JT Mitochondrial DNA damage: molecular marker of vulnerable nigral neurons in Parkinson’s disease, Neurobiol Dis 70:214-223, 2014. PMC4144978

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

Di Maio R, Barrett PJ, Hoffman EK, Barrett C, Zharikov A, Borah A, Hu X, McCoy J, Chu CT, Burton EA, Hastings TG and Greenamyre JT, α-Synuclein binds TOM20 and inhibits mitochondrial protein import in Parkinson’s disease, submitted.

More publications

Lab Members

  • Paul Barett, PhD

    Postdoctoral Fellow

    barretpj@upmc.edu

    I am a post-doctoral fellow who investigates how the protein alpha Synuclein impairs mitochondrial protein import in Parkinson's disease. We are specifically interested in how different post-translationally modified and mutated forms of alpha Synuclein interact with proteins involved in mitochondrial import. By gaining a better understanding of how alpha Synuclein impairs mitochondrial import, we will begin to understand the mechanisms leading to mitochondrial dysfunction and cell death in Parkinson's disease

  • Briana De Miranda, PHD

    Postdoctoral Fellow

    demirandabr@upmc.edu

    The goal of my research at the Pittsburgh Institute for Neurodegenerative Diseases is to explore therapeutic strategies of gene therapy in Parkinson’s disease, and target pathological mechanisms that may be mitigated to slow the progression of dopamine neuron death. There is a rapidly expanding focus on the role of glial cells in PD disease progression, with several lines of evidence indicating that glia may enhance neuroprotection through their support function, but also may contribute to neurotoxicity upon unregulated inflammatory conditions.

  • Roberto Di Maio

    Research Associate

    rod16@pitt.edu

    Dr. Di Maio’s research focuses on defining the oxidative stress-related mechanisms of neurodegeneration. Using in vitro and in vivo experimental models of neuronal damage, his main goal is to assess the pathogenic pathways as potential targets for novel therapeutic approaches aimed at the prevention and/or cure of neurodegenerative disorders, such as Parkinson’s disease and epilepsy.

  • Eric Hoffman

    Assistant Professor

    hoffmanek@upmc.edu

    My research focuses on the study of genes implicated in Parkinson’s disease as a means of developing cell culture-based models for this disorder. CRISPR/Cas9 genome editing methods are being utilized to generate gene knockout and knock-in cell lines, enabling further studies addressing how expression of these genes may contribute to the disease process.

  • Evan Howlett

    Research Technician

    howletteh@upmc.com
  • Xiaping Hu

    Research Technician

    xhcz2@pitt.edu
  • Nick Jensen

    Research Technician

    nij18@pitt.edu
  • Jillian Kluss

    Undergraduate Researcher

    jhk33@pitt.edu

    Jillian works with human white blood cells from both PD patients and healthy controls. Through techniques such as immunocytochemistry and Western Blots, she works to discover a systemic biomarker for PD as well as uncover parts of the pathology's mechanism.