Ruth Glanville Perez received her B.S. and M.A. degrees from the University of Texas at El Paso and Ph.D. from the University of Pittsburgh School of Medicine, Department of Neurobiology. After postdoctoral training in Boston at the Center for Neurologic Diseases in the Department of Neurology at Brigham & Women’s Hospital, Harvard Medical School she joined the faculty of Allegheny Singer Research Institute, Medical College of Pennsylvania Hahnemann, Allegheny University of the Health Sciences in Pittsburgh, PA. She returned to the University of Pittsburgh in the fall of 1999 as Research Assistant Professor of Neurology; and was promoted to Assistant Professor of Neurology in 2005. In 2010, she was promoted to Associate Professor of Neurology with a secondary appointment in the Department of Pharmacology and Chemical Biology. The following year, she returned to El Paso as Associate Professor of Biomedical Sciences in the Graduate School of Biomedical Sciences at Paul L. Foster School of Medicine. Her laboratory is doing cutting edge translational research on neurodegenerative diseases, searching for cures for Parkinson’s disease and related neurological disorders. Her research has been funded by the National Institute of Neurological Disorders and Stroke, National Institute on Aging, Scaife Family Foundation, Pittsburgh Foundation, Pittsburgh Parkinson’s Chapter, Michael J. Fox Foundation, Ethyl Vincent Charitable Trust, Alzheimer’s Association, Lizanell and Colbert Coldwell Foundation, in addition to seed grants from the Office of the Associate Dean for Research at Texas Tech University Health Sciences Center at El Paso.
The Perez lab is working to identify the normal functions of aggregation-prone proteins that cause neurodegenerative diseases. Using biochemistry, cell biology, molecular biology, and mouse behavioral models her laboratory measures the impact of the proteins on cell signaling, neuronal and glial function, enzymatic activity and protein phosphorylation. Key projects focus on the proteins α-synuclein and 14-3-3, two chaperone-like molecules that work in counterpoint to each other to regulate other proteins that they both bind. Most research is related to Parkinson’s disease, with other studies focusing on Dementia with Lewy Bodies, Alzheimer’s disease, Multiple System Atrophy, and Diabetes. With regard to Parkinson’s disease, the Perez lab discovered that α-synuclein, which is highly implicated in Parkinson’s disease pathology, is a key regulator of dopamine, the neurotransmitter that controls movement, affect, olfaction, and cognition. α-Synuclein inhibits the activity of tyrosine hydroxylase, the rate limiting enzyme for dopamine synthesis. Dopamine levels must be tightly regulated because the neurotransmitter is toxic when not sequestered in secretory vesicles.
Another regulatory property of α-synuclein is an ability to bind and stimulate the catalytic activity of protein phosphatase 2A (PP2A), a key dephosphorylating enzyme. PP2A dephosphorylates tyrosine hydroxylase to reduce its activity. Furthermore, the Perez lab found that if α-synuclein aggregates in Lewy bodies, PP2A activity becomes coordinately reduced. That could allow hyperphosphorylation of tyrosine hydroxylase and other substrates such as tau, the small microtubule associated cytoskeletal protein that when hyperphosphorylated forms neurofibrillary tangles inside neurons of Alzheimer disease. Many other proteins are substrates for PP2A.
Additional data from the lab demonstrate that α-synuclein inhibits insulin release from pancreatic beta cells by interactions with the potassium channel, Kir6.2. Other studies explore: (1) function of the amyloid precursor protein (APP); (2) the role of the Low Density Lipoprotein Receptor-related Protein (LRP) in neuron function; and (3) the impact of α-synuclein on glial cells as it relates to Multiple System Atrophy. Together these projects are a concerted effort to identify therapeutic targets to help optimize brain function and enhance the quality of life for everyone, but especially for the aging population worldwide.
Back L-R - Wesley Godfrey, Ismael Segura, Dr. Javier Vargas-Medrano, Sesha Krishnamachari Front L-R - Gloria Herrera, Samantha Dominguez, Dr. Guadalupe Vidal, Dr. Perez, Gabby Benuska, Maria Garcia, Dr. Carolina Gil
Above Left - Members of the Perez Lab, March 2014. Back row near the wall, L to R, Sesha Krishnamachari, Ismael Segura, Maria Garcia, and Dr. Carolina Gil. Front row, L to R, Samantha J. Dominguez, Dr. Guadalupe Vidal, Gloria Herrera and Dr. Javier Vargas-Medrano. Above Right – Dr. Perez with her team on the campus of Texas Tech University Health Sciences Center at El Paso.
Drs. Hugo Sandoval, Donald E. Moss and Ruth G. Perez on the campus of el Technológico de Monterrey, Chihuahua, Chihuahua, México; where they presented seminars on their research at El Congréso de Bioenginieréa, April 3, 2014.
Left, Jose Luis (Tito) Porras, Center, L to R, Sesha Krishnamachari, Tito Porras, Ernesto Villanueva, Right, Drs. Javier Vargas-Medrano and Guadalupe (Lupe) Vidal celebrating Cinco de Mayo at the Biomedical Sciences Departmental Luncheon, May 2013.
Novel FTY720-based compounds stimulate neurotrophin expression and phosphatase activity in dopaminergic cells. http://dx.doi.org/10.1021/ml500128g Vargas-Medrano J, Krishnamachari S, Villanueva E, Godfrey WH, Lou H, Chinnasamy R, Arterburn JB, Perez RG. ACS Med Chem Lett. 2014 May.
Non-motor parkinsonian pathology in aging A53T alpha-synuclein mice is associated with progressive synucleinopathy and altered enzymatic function. Farrell KF, Krishnamachari S, Villanueva E, Lou H, Alerte TN, Peet E, Drolet RE, Perez RG. J Neurochem. 2014 Feb; 128(4):536-46.
Potential contribution of α-synuclein dysregulation to Parkinson’s disease pathology. Mini review, Chapter III. In: Alpha-Synuclein: Functional Mechanisms, Structure and Role in Parkinson’s Disease, (Eds.) Porras JL, Perez RG Nova Science Publishers, Inc., Hauppauge, NY, 2014.
APP independent and dependent effects on neurite outgrowth are modulated by the receptor associated protein (RAP). Billnitzer AJ, Barskaya I, Yin C, Perez RG. J Neurochem. 2013 Jan; 124(1):123-32.
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.
α-Synuclein binds the K(ATP) channel at insulin-secretory granules and inhibits insulin secretion. Geng X, Lou H, Wang J, Li L, Swanson AL, Sun M, Beers-Stolz D, Watkins S, Perez RG, Drain P. Am J Physiol Endocrinol Metab. 2011 Feb; 300(2):E276-86.
Serine 129 phosphorylation reduces the ability of α-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; 285(23):17648-61.
14-3-3 zeta 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.
α-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; 435(1):24-9.
α-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.