Our laboratory has a longstanding interest in the pathogenic processes in Alzheimer's disease (AD) and central nervous system (CNS) injury. 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. Currently studies in our lab are focused in two areas: (1) on understanding the regulation and function of the protein in tau in the context of AD, and (2) on how a protein called transglutaminase 2 (TG2) differentially impacts the survival and function of neurons and astrocytes following CNS injury. Each of these two areas of research that are ongoing in our lab is discussed briefly below.
The neuronally enriched protein tau plays a primary role in the pathogenesis of AD. Indeed, abnormal accumulations of aberrantly modified forms of the protein, neurofibrillary tangles, are one of the defining hallmarks of the disease. However, why the levels of these pathogenic forms of tau increase in AD, and how they cause toxicity are questions that have not been satisfactorily answered. A major focus of our studies involves determining how a neuron recognizes tau that is abnormally modified or no longer functional, and targets it to the autophagy pathway for degradation. In particular our group is interested in determining if a complex containing the co-chaperone BAG3 and other interacting proteins plays a role in not only directing tau to autophagy, but also in mediating the autophagy process. Further, our lab is also investigating how pathologically relevant forms of tau impact mitochondrial biology and the general health/functioning of the neuron.
Our lab also has a well-established interest in understanding the regulation and function of TG2 in neuronal cell death and survival. We have found that in neurons TG2 localizes to the nucleus in response to stress and plays a protective role. Intriguingly the converse is true for TG2 in astrocytes where it plays a detrimental role. Knockdown or deletion of TG2 from astrocytes significantly increases survival after stress and significantly increases their ability to protein neurons from insults. Given these and other findings we are currently delineating the differential roles of TG2 in regulating gene expression profiles in neurons and astrocytes. We are also examining how selective deletion of astrocytic TG2 improves outcomes after spinal cord injury, as well as investigating selective TG2 inhibitors as possible therapeutic interventions in the treatment of spinal cord injury.
