The pathogenic role of protein aggregation in inflammatory demyelination

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DESCRIPTION (provided by applicant): Our long-term goal is to define and characterize the mechanisms underlying tissue injury in multiple sclerosis (MS), the most common demyelinating disease of the central nervous system in humans. In recent years, oxidative stress has been implicated in the pathophysiology of both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Previous studies from our laboratory have shown that MS and EAE, like several other neurological disorders, are characterized by the accumulation of carbonylated (oxidized) proteins within CNS cells. We have also demonstrated that the build-up of oxidized and other misfolded proteins in these disorders is a consequence of decreased activity of the proteasome, the proteolytic machinery responsible for their removal. Carbonylation and other oxidative protein modifications are known to cause inappropriate inter- and intra-protein cross-links as well as protein misfolding. This, in turn, results in the formation of protein aggregates that we believe contribute to the demise of neural cells and ultimately tissue damage. Indeed, we have obtained preliminary evidence that aggregates containing oxidized proteins accumulate in the CNS of MS patients and EAE mice and that inhibition of protein aggregation prevents neuronal cell death in culture. Based on these novel findings, we hypothesize that protein aggregation plays a pathogenic role in EAE. To test this idea, we will (1) quantify the temporal/spatial pattern of protein aggregation and its relationship to the extent of neuronal and oligodendroglial cell death in the spinal cord during the course of MOG peptide-induced EAE, and (2) examine the prophylactic and therapeutic efficacy of two chemically- distinct protein aggregation inhibitors at preventing cell death and tissue injury and at reducing neurological symptoms of EAE. If successful, these studies will not only demonstrate that protein aggregation is pathogenic in inflammatory demyelinating disease but also will provide the basis for developing new or testing previously identified non-toxic aggregation inhibitors for an improved clinical management of MS.