Research: Center of Excellence for Neuroscience
Ruth Perez, Ph.D.
Associate Professor, Department of Biomedical Sciences and Center of Excellence for Neuroscience
Department of Biomedical Sciences
Ruth Perez received her B.S. and M.A. degrees from the University of Texas at El Paso and her Ph.D. from the University of Pittsburgh School of Medicine. After postdoctoral training at the Center for Neurologic Diseases at Brigham and Women’s Hospital of Harvard Medical School she joined the faculty of the Allegheny Singer Research Institute, Medical College of Pennsylvania Hahnemann at Allegheny University of the Health Sciences. She returned to the University of Pittsburgh in 1999 and obtained a tenure stream faculty appointment in 2005. In 2010 she was promoted to Associate Professor of Neurology and had a secondary appointment in the Department of Pharmacology and Chemical Biology. In August of 2011, Dr. Perez returned to El Paso where she is Associate Professor of Biomedical Sciences at the Paul L. Foster School of Medicine. Her laboratory does basic science and translational research on neurodegenerative diseases with a focus on Parkinson’s disease and related disorders. Funding has been provided by the National Institute of Neurological Disorders and Stroke, National Institute on Aging, Michael J Fox Foundation, Ethyl Vincent Charitable Trust, Alzheimer’s Association, Scaife Family Foundation, and the Pittsburgh Foundation.
The Perez lab studies the normal function of the key proteins that “go bad” in brain disorders. Using biochemistry, cell biology, molecular biology, and mouse models the lab measures the effects of proteins on cell signaling, neuronal function, enzymatic activity and protein phosphorylation. Major projects focus on the contributions of alpha-synuclein and 14-3-3 proteins, two chaperone-like molecules that work in counterpoint to each other to regulate proteins with which they interact. Key projects on Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB), Alzheimer’s disease (AD), and diabetes are in progress. With regard to PD, the Perez lab showed that alpha-synuclein, a protein strongly implicated in PD, is a normal regulator of dopamine synthesis, a brain neurotransmitter that contributes to olfaction, body movements, affect, and cognition. Alpha-synuclein inhibits the rate limiting dopamine synthesis enzyme, tyrosine hydroxylase. Dopamine is tightly regulated because it can be is toxic if overproduced and present in the cytosol. Another major regulatory property of alpha-synuclein is its ability to interact with and stimulate the activity of the catalytic subunit of protein phosphatase 2A (PP2A). PP2A dephosphorylates tyrosine hydroxylase and many other brain proteins. Additional data from the lab demonstrate that alpha-synuclein contributes to the release of insulin from pancreatic beta cells by interacting with the inwardly rectifying potassium channel, Kir6.2. DLB studies reveal that alpha-synuclein aggregation impairs PP2A activity, which then allows hyperphosphorylation of tyrosine hydroxylase as well as tau, a small cytoskeletal protein that forms neurofibrillary tangles in AD brains. Those studies align with Alzheimer-related projects to elucidate the normal function of the amyloid precursor protein (APP) and the role of the Low Density Lipoprotein Receptor-related Protein (LRP) in neuronal development. Together these projects form a concerted effort to identify novel targets for improving brain function to optimize the quality of life for patients with synucleinopathy. New studies reveal potential new compounds to reverse alpha-synuclein related neuropathology.
- Lewy-like aggregation of α-synuclein reduces protein phosphatase 2A activity in vitro and in vivo. Wu J, Lou H, Alerte TN, Stachowski EK, Chen J, Singleton AB, Hamilton RL, Perez RG. Neuroscience. 2012 Apr 5;207:288-97. Epub 2012 Jan 25. PMID: 22326202
- Serine 129 phosphorylation reduces the ability of alpha-synuclein to regulate tyrosine hydroxylase and protein phosphatase 2A in vitro and in vivo. Lou H, Montoya SE, Alerte TN, Wang J, Wu J, Peng X, Hong CS, Friedrich EE, Mader SA, Pedersen CJ, Marcus BS, McCormack AL, Di Monte DA, Daubner SC, Perez RG. J Biol Chem. 2010 Jun 4; 285(23):17648-61.
- 14-3-3zeta contributes to tyrosine hydroxylase activity in MN9D cells: localization of dopamine regulatory proteins to mitochondria. Wang J, Lou H, Pedersen CJ, Smith AD, Perez RG. J Biol Chem. 2009 May 22; 284(21):14011-9.
- Alpha-synuclein aggregation alters tyrosine hydroxylase phosphorylation and immunoreactivity: lessons from viral transduction of knockout mice. Alerte TN, Akinfolarin AA, Friedrich EE, Mader SA, Hong CS, Perez RG. Neurosci Lett. 2008 Apr 11; 435(1):24-9.
- Phosphorylation of beta-amyloid precursor protein (APP) cytoplasmic tail facilitates amyloidogenic processing during apoptosis. Sodhi CP, Perez RG, Gottardi-Littell NR. Brain Res. 2008 Mar 10; 1198:204-12.
- Alpha-synuclein inhibits aromatic amino acid decarboxylase activity in dopaminergic cells. Tehranian R, Montoya SE, Van Laar AD, Hastings TG, Perez RG. J Neurochem. 2006 Nov; 99(4):1188-96.
- Alpha-synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells. Peng X, Tehranian R, Dietrich P, Stefanis L, Perez RG. J Cell Sci. 2005 Aug 1; 118(Pt 15):3523-30.
- Could a loss of alpha-synuclein function put dopaminergic neurons at risk? Perez RG, Hastings TG. J Neurochem. 2004 Jun; 89(6):1318-24. Review.