Gail V W Johnson, Ph.D.

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.

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