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Protein Misfolding Diseases
An increasingly growing number of diseases are caused by alterations in the folding, processing, localization, or degradation of proteins that traffic through the secretory pathway. However, the molecular mechanisms that underlie either the aberrant protein processing events or the downstream consequences for cellular function remain largely unknown. To gain insight into these questions, several members of our lab are studying the mammalian Prion protein (PrP), a cell surface glycoprotein whose aberrant metabolism causes several neurodegenerative diseases in both people and animals. These diseases include the transmissible 'prion diseases' such as bovine spongiform encephalopathy, as well as inheritable neurodegenerative diseases caused by mutations in the PrP gene. In neither case are the pathways leading to cell death and neuronal damage understood.
Our overall goals are to define these pathways of PrP-mediated neurodegeneration. We are analyzing a broad panel of disease-causing PrP mutants to identify shared aberrations in their trafficking or metabolism that would provide clues to their causative role in neurodegeneration. When and where do PrP mutants diverge from wild type PrP trafficking and metabolism? What quality control mechanisms operate on wild type and mutant PrPs? What are the consequences of mutant PrP accumulation for cellular function? Can the biosynthetic, quality control, or degradation pathways be manipulated to influence the course of neurodegeneration? These and other questions are being addressed using a combination of in vitro systems, biochemical and high resolution imaging analyses of cultured cells, and genetically modified mouse models.
