Our research is focused on glycosylphosphatidylinositol (GPI)-anchored proteins. This type of proteins participates in many important cellular functions, including immune recognition, complement regulation, and intracellular signaling. In addition, GPI-anchored proteins have been shown to play an important role in a variety of diseases ranging from the hemolytic disorder Paroxysmal Nocturnal Hemoglobinuria to neurodegenerative diseases, such as prion diseases and Alzheimer?s disease. Among other properties the GPI anchor targets the attached proteins to membrane microdomains enriched in cholesterol and glycosphingolipids known as ?lipid rafts?. Interestingly, it appears that the contribution of GPI-anchored proteins to the overall pathology observed in some of these diseases depends on the ability of these proteins to partition in lipid rafts.
Currently, we are investigating the role of lipid rafts and GPI-anchored proteins in neurodegenerative diseases. One area of investigation in our lab is centered on the role of GPI-anchored proteins in Alzheimer?s disease. In vitro and in vivo approaches are being used in these studies. The in vitro approach is focused on the generation and toxicity of the a-beta peptide, the main component of amyloid plaques in the brain of Alzheimer?s disease patients. GPI-anchored proteins (our studies) and caveolin have been shown to influence a-beta synthesis that was proposed to occur in lipid rafts. We are studying the mechanism by which caveolin affects a-beta levels to determine if it is via downregulation of GPI-anchored proteins. The in vivo studies are centered on the role of inflammation in Alzheimer?s disease pathology. Contrary to an established dogma recent reports suggest that activation of complement, a key initiator of inflammation, results in ameliorated pathology. We are exploring this issue using animals in which the expression of two GPI-anchored complement regulatory proteins, decay accelerating factor and CD59 has been knockout.
A second area of research is focused on the role of lipids rafts in neurodegenerative disorders characterized by the presence of brain synuclein inclusions. Using cell and animal models we plan to modulate the pool of synuclein present lipid rafts and assessed its impact on synuclein aggregation and on the pathology.