Skip to main content
Explore URMC

URMC Logo

menu
URMC / Labs / Gail Johnson Lab

Gail Johnson Lab

Johnson Lab

The primary focus of Dr. Gail Johnson’s research group is on the molecular mechanisms of neurodegeneration. The lab has a longstanding interest in the pathogenic processes in Alzheimer disease, and more recently in stroke and spinal cord injury (SCI). For their studies they 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 them to translate what they learn about a process or signaling pathway at the molecular level to the in vivo situation. Each of these 2 areas of research that are ongoing in the lab are discussed briefly below.

A hallmark of the Alzheimer disease brain is the presence of the intracellular neurofibrillary tangles composed primarily of the protein tau in a pathologically modified state. There is compelling evidence that the accumulation of tau with aberrant posttranslational modifications is central to the disease process and that the abnormally modified tau is toxic to neurons. This increased accumulation of tau is likely due in part to inefficient clearance mechanisms.  Therefore an understanding of the proteolytic processes that degrade and remove tau from neurons is needed.  In this context a primary focus of our lab is on delineating the mechanisms involved in clearing tau from neurons.  Based on previous studies it is clear that autophagy is a primary degradative pathway in neurons.  We and others have provided evidence that tau is degraded by autophagy, but the processes involved have not been clearly identified.  Currently ongoing research in the lab is directed towards understanding how tau is selectively targeted to autophagy for degradation and how these processes could be dysregulated in Alzheimer disease.

The Johnson lab also has a well-established interest in understanding the regulation and function of transglutaminase 2 (TG2) in neural cell death and survival, particular in the context of central nervous system injury.  They have found that in neurons TG2 promotes survival subsequent to ischemic injury and this is dependent on TG2 localization to the nucleus.  Interestingly, TG2 in astrocytes has the opposite effect as it plays a detrimental role in injury responses.  Deletion or inhibition of TG2 from astrocytes significantly increases their ability to survive stress-induced cell death and to protect neurons from oxygen and glucose deprivation-induced cell death.   They are now investigating the mechanisms by which TG2 attenuates ischemic-induced cell death in astrocytes and their protective response, but increases the survival of neurons.

Within the framework of each of these projects there are numerous opportunities for rotation projects.  In the context of tau and Alzheimer disease project rotation projects could include: identifying the interactors in the complex that targets tau for autophagic degradation, delineating how different protein complexes orchestrate the maturation of the autophagic vacuoles or determining if certain differentially modified forms of tau are preferentially cleared by autophagy.  In the context of the role of TG2 in differentially mediating cell survival processes in neurons and astrocytes rotation projects could include: determining how TG2 is mediating transcriptional repression in neurons and what signaling pathways are being predominantly affected and determining how and whyTG2 in astrocytes mediates detrimental responses to ischemia.

Research Opportunities for residents

The Basic Science Division within the Department of Anesthesia wishes to invite faculty or residents to participate in a research project examining potential mechanisms for post-operative cognitive dysfunction after anesthesia. Postoperative cognitive dysfunction in the elderly is a common occurrence. Patients with Alzheimer disease (AD) are particularly at risk for the development of postoperative cognitive dysfunction. There are also studies suggesting that exposure to anesthesia may increase the risk of AD. 

Intraneuronal neurofibrillary tangles composed of cleaved and hyperphosphorylated tau are a pathological hallmark of the Alzheimer disease (AD)brain. The abnormal cleavage and hyperphosphorylation of tau is a pivotal event in the neurodegenerative process in AD. However, it is not clear how these pathological forms of tau facilitate neuronal cell dysfunction and death. Recent studies have shown in mouse models that exposure to anesthetics results in persistent increases in tau phosphorylation, however the mechanisms involved remain unclear, and have been suggested to be due to the hypothermia rather than the anesthesia per se. 

In this project a cellular model approach will be used to determine whether anesthesia alone, hypothermia alone or the combination of the two effect tau phosphorylation and function. Analyses will involve immunocytochemistry, immunoblotting, cell viability measures and fractionation assays.

Research Funding

Bright Focus Foundation

Nrf2 regulates tau clearance: an AD treatment strategy

NIH

R56NS094086: The degradation of tau by selective autophagy

PubMed Publication List

Research Publications

Lei, Z., Brizzee, C.O. and Johnson, G.V.W. 2014. BAG3 facilitates the clearance of endogenous tau in neurons, Neurobiology of Aging, Aug 16. pii: S0197-4580(14)00525-9. doi: 10.1016/j.neurobiolaging.2014.08.012. [Epub ahead of print]. PMID: 25212465.

Chesser, A.C., Ganeshan, V., Yang, J. and  Johnson, G.V.W. 2016. Epigallocatechin-3-gallate enhances clearance of phosphorylated tau in primary neurons, Nutritional Neuroscience, Jan;19(1):21-31. doi: 10.1179/1476830515Y.0000000038. Epub 2015 Jul 24.

Pallo, S.P., Cook, A., DiMaio, J. Nilsson, B. and Johnson, G.V.W. 2015.  Tau and Aβ contribute to Alzheimer’s disease related excitotoxicity. Brain Research, Dec 28. pii: S0006-8993(15)00987-7. doi: 10.1016/j.brainres.2015.12.048. [Epub ahead of print].

Feola, J., Monteagudo, A., Yunes-Medina, L. and Johnson, G.V.W. 2015.  Transglutaminases and Neurological Diseases, in Transglutaminases: Multiple Functional Modifiers and Targets for New Drug Discovery, Editors: Kiyotaka Hitomi, Soichi Kojima, and Laszlo Fesus, Springer Publishing, New York, NY.

Quintanilla, R.A., Cabezas-Opazo, F., Pallo, S.P., Chesser, A.S. and Johnson, G.V.W. 2016. Chapter 13, Stimulation of Tau Degradation, in Developing Therapeutics for Alzheimer’s Disease: Progress and Challenges, Editor:  Michael S. Wolfe, Elsevier Publishing, Waltham, MA.

Gundemir, S., Monteagudo, A., Akbar, A., Keillor, J.W. and Johnson, G.V.W., 2016. The complex role of transglutaminase 2 in glioblastoma proliferation.  Neuro-Oncology, in press. 

Kim, S., Choi, K., Cho, S.-J., Yun, S.-M., Jeon, J.-P., Koh, Y., Song, J., Johnson, G.V.W. and Jo, C. 2016. Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors. Scientific Reports 6:24933 | DOI: 10.1038/srep24933.