Grant: CIHR Fellowship

Prion diseases are fatal neurodegenerative diseases which affect both humans and animals. Bovine spongiform encephalopathy (BSE), also known as Mad Cow Disease, is the most widely known of this family. These diseases are caused by the prion protein (highly abundant in the central nervous system) which has been altered from its normal form, which does not cause disease, into a disease-causing form. Part of the prion protein's normal function in healthy individuals is regulating vitally important trace metals in the brain and nervous system. We have demonstrated, using synchrotron-based imaging, that changing how much prion protein is produced disrupts levels of naturally-occurring copper, iron and zinc in the brain - indicating that the prion protein is part of the integral cellular machinery for regulating metals in the nervous system. We hypothesize that similar disruptions are likely present in individuals with prion disease and that disrupted brain metal content could be an exacerbating factor of other neurodegenerative diseases. Using a combination of synchrotron-based X-ray techniques (such as those available at the Canadian Light Source synchrotron at U. Saskatchewan) to map metals in the brain, as well as computational chemistry and positron emission tomography (PET) we are developing detailed pictures of how changes in metals at the molecular and atomic level influence the anatomic level. Altered trace metal levels in the brain are a common feature in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases as well as metal storage disorders such as Wilson's disease and hemochromatosis. Understanding how metals are disrupted in prion disease may be beneficial for understanding how disrupted metal levels affect neurodegeneration in general. Detailed molecular and anatomic knowledge of which metals and regions of the brain are preferentially affected in individuals is vital to devise custom therapies and individualized treatments.