Enhancing the unfolded protein response as a protective therapy for multiple sclerosis

Our overall goal in this proposal is to better understand the response of oligodendrocytes to inflammatory attacks so that oligodendrocyte protective therapies can be developed. Protection of oligodendrocytes will allow for the preservation of myelin production and promote myelin repair. Previous studies have shown that a protective response is triggered to cope with stress in oligodendrocytes during inflammatory attacks. In this response, the body shuts down myelin production and prompts the oligodendrocyte to produce beneficial proteins to help remove the abnormal myelin. When faced with inflammatory attacks similar to those in MS, however, oligodendrocytes severely ramp up production in an attempt to repair all the damaged myelin, to the point where the protective response is not sufficient to save the oligodendrocyte from dying. In this proposal, we seek to understand how this oligodendrocyte death can be prevented. Toward this goal, we will measure the therapeutic effects of small chemical compounds that are designed to enhance this protective response in a well-established self-myelin antigen induced mouse model and a toxin-induced inflammatory model of MS. Furthermore, we will explore the mechanism by which the oligodendrocytes die, called autophagy, in regulating this protective response in oligodendrocytes during the inflammatory attacks.