About The Lab
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.