Gail V W Johnson, Ph.D.

Gail V W Johnson, Ph.D.

Contact Information

University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 604
Rochester, NY 14642

Office: (585) 276-3740
Fax: (585) 276-2418

Research Bio

THE MOLECULAR MECHANISMS OF NEURODEGENERATION
gail_johnsonvoll@urmc.rochester.edu



Our laboratory has a longstanding interest in the pathogenic processes in Alzheimer disease and Huntington disease, and more recently in stroke. For our studies we use a wide variety of different approaches from in vitro enzyme assays with purified proteins, to studies in whole animals. This broad-based approach allows us to translate what we learn about a process or signaling pathway at the molecular level to the in vivo situation. Each of the 3 areas of research that are ongoing in our lab is discussed briefly below.
Two hallmarks of the Alzheimer's disease brain are the intracellular neurofibrillary tangles composed primarily of the protein tau in a pathologically modified state and the extracellular senile plaques composed primarily of the Abeta peptide. There is compelling evidence that aberrant posttranslational processing of tau is central to the disease process. Nonetheless, the mechanisms by which pathological changes in tau result in impaired neuronal function and contribute to cell death processes in Alzheimer disease have not been fully elucidated. A major focus in our lab is on understanding the cellular targets of Alzheimer disease relevant forms of tau. Currently we are investigating how tau that is abnormally phosphorylated and/or proteolytically processed impacts mitochondrial dynamics and function. We and others have exciting new data suggesting that the mitochondria may be a crucial downstream target of pathological tau and contribute to the neurodegenerative processes.
Our lab has a well-established and longstanding interest in understanding the regulation and function of transglutaminase 2 (TG2) in neuronal cell death and survival. Recently we found that TG2 in its capacity as a scaffold protein binds HIF1beta, attenuates HIF signaling, attenuates the expression of specific HIF responsive pro-apoptotic genes and protects neurons from ischemia-induced cell death. In addition, we have found that exogenous expression of TG2 in neurons in a mouse is protective against stroke damage. Therefore we are investigating the mechanisms by which TG2 attenuates HIF signaling and protects against ischemia-induced cell death.

Huntington disease is an autosomal dominant neurodegenerative disease caused by a pathological expansion of the polyglutamine domain in the huntingtin protein. There is convincing evidence that both transcriptional dysregulation and mitochondrial dysfunction play pivotal roles in the pathogenesis of Huntington disease. In recent studies we have found that mitochondria from mutant huntingtin expressing striatal cells take up significantly less calcium than mitochondria from wild type cells and are significantly more sensitive to calcium-induced decreases in respiration. We have also found that the expression of specific mitochondrial and anti-oxidant genes are downregulated in Huntington disease cell models. Therefore we are now investigating: (1) whether mutant huntingtin impairs the ability of mitochondria to appropriately maintain pH and regulate redox status and if this contributes to the calcium handling defects that result in respiratory deficits and increased sensitivity to calcium-induced permeability transition pore opening, (2) whether a decrease in the transcriptional activity PPARgamma by mutant huntingtin compromises mitochondrial metabolism and function and (3) whether activation of PPARgamma ameliorates mitochondrial dysfunction in mouse Huntington's disease models.

Awards & Honors (Local)

Ruth K. Broad Biomedical Research Foundation, Inc. Awardee 1994 - 1996
Ciba Foundation Fellow Sponsor 1992
NIH First Award 1989 - 1994

Recent Journal Articles

Showing the 5 most recent journal articles. 171 available »

2009
Quintanilla, R.A., Matthews-Roberson, T.A., Dolan, P.J. and Johnson, G.V.W. "Caspase-cleaved tau expression results in mitochondrial dysfunction in cortical neurons. Implications for the pathogenesis of Alzheimer disease". Journal of Biological Chemistry. 2009; 284: 18754-18766. Link
2009
Beagle, B.B., Mi, K. and Johnson, G.V.W. "Phosphorylation of PPP(S/T)P motif in non-membrane anchored LRP6 intracellular domain is not required to activate the Wnt/beta-Catenin pathway and attenuate GSK3beta activity". Journal of Cellular Biochemistry. 2009; 108: 886-895. Link
2009
Quintanilla, R.A. and Johnson, G.V.W. "The role of mitochondrial dysfunction in Huntington disease". Brain Research Bulletin. 2009; 80: 242-247. Link
2009
Gundemir, S. and Johnson, G.V.W. "Intracellular localization and conformational state of transglutaminase 2: Implications for cell death". PlosOne. 2009; 4(7): e6123. Link
2008
Filiano, A.J., Bailey, C.D.C., Tucholski, J. Gundemir, S. and Johnson, G.V.W. "Transglutaminase 2 protects against ischemic insult, interacts with HIF1beta and attenuates HIF signaling". FASEB Journal. 2008; : 2662-2675. Link

Current Appointments

Professor - Department of Anesthesiology (SMD) - Primary
Professor - Department of Pharmacology and Physiology (SMD)
Professor - Center for Neural Development & Disease

Education

Ph.D. | Physiology | University of Delaware1984
M.S. | Entomology | University of Massachusetts1978
B.A. | Biology | Southampton College1976

Post-Doctoral Training & Residency

Postdoctoral Research Fellow, Department of Pharmacology, University of Alabama at Birmingham (UAB), Birmingham, AL 1988