Common diseases that generally are not passed on by Mendelian genetics can be better understood and treated by taking advantage of the fact that there are rare familial forms of the disease. For example, most cases of Alzheimer's Disease are sporadic, or not caused by a single genetic mutation. However, there are families in which members develop the disease at much higher rates than the general population, and from these families or cohorts, we have learned about genetic variants in APP, presenilin and ApoE that predispose to disease. In our lab, we are interested in all parts of the process of describing, identifying and researching diseases, but we are most actively engaged in the parts of the process that are highlighted in red. Specifically, we study how variations in the progranulin and MAPT/tau genes can lead to particular disease phenotypes. To do so, we have taken advantage of the strong molecular genetic techniques available in C. elegans and then confirmed and extended our findings in mammalian models. Our goal is to translate our findings into treatments and even preventions for neurodegenerative diseases like Alzheimer's Disease, frontotemporal dementia and related disorders.
Progranulin and regulation of programmed cell death kinetics
Mutations in progranulin lead to the development of frontotemporal lobar degeneration, a devastating neurodegenerative disease. Disease-related progranulin mutations result in a genetic haploinsufficiency, or production of progranulin protein levels that are approximately half that of normal. Apoptosis or programmed cell death is a normal process of removal of excess, unnecessary or damaged cells. Using the nematode C. elegans and cultured murine cells, we recently discovered that loss of progranulin affects the rate of clearance of apoptotic cells. One project in the lab is to better understand how progranulin regulates programmed cell death kinetics and how progranulin deficiency leads to neurodegeneration. Future work will involve understanding the effects of progranulin on microglial function and interrogating the relative roles for granulin versus progranulin.
Pathophysiological implications of the MAPT A152 polymorphism
Mutations in the MAPT or tau gene have been associated with several neurodegenerative diseases and tau "tangles" are found in the brains of those afflicted with Alzheimer's Disease. Recently, a polymorphism in MAPT at position 152 has been described. We are characterizing the effect of this variant by overexpressing human A152T in C. elegans and observing changes in nematode behavior as well as biochemical characteristics of tau such as post-translational modification and protein-protein interactions. We are also utilizing state of the art CRISPR/Cas gene editing techniques in human induced pluripotent stem cells to explore the influence of disease-associated polymorphisms on genotype-phenotype interactions.