Targeting the Integrated Stress Response to Protect Oligodendrocyte lineage Cells

The focus of the studies funded by this award over the past two decades has been on the response of oligodendrocytes to inflammation. This work is of critical relevance to the immune-mediated demyelinating disorder multiple sclerosis, which is characterized by CNS inflammation, oligodendrocyte loss, demyelination and axonal degeneration. Our studies have shown that oligodendrocytes respond to inflammation by activating the integrated stress response (ISR), which is a highly conserved, cytoprotective response that initiates with the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α). We have demonstrated using genetic models that oligodendrocytes with a diminished capacity to phosphorylate eIF2α in response to stress display increased susceptibility to inflammatory insults and that prolonging the phosphorylated state of eIF2α in oligodendrocytes increases their resistance to inflammation, both in vitro and in mouse models of inflammatory demyelination. This work has provided the foundation for an effort to protect oligodendrocytes from inflammation by pharmacologically enhancing the ISR. In contrast, recent reports indicate that that the inhibition of the ISR pathway provides protection in certain neurological disorders. Moreover, our unpublished work indicates that oligodendrocytes experiencing ER stress activate a distinct cytoprotective response from oligodendrocytes challenged by mediators of inflammation. The studies described in the current proposal are designed to uncover the molecular origin of this dichotomy. In aim 1 we will carry out a detailed characterization of the oligodendroglial stress response in Jimpy mutant mice, which represent a mouse model of the human leukodystrophy Pelizaeus-Merzbacher disease. Jimpy oligodendrocytes experience severe ER stress, and our preliminary data indicates that inhibiting ISR activation in these animals provides significant protection to oligodendrocytes. In aim 2 we will directly compare the various aspects of the response of oligodendrocytes experiencing ER stress with oligodendrocytes exposed to inflammation. Aims 3 and 4 will be devoted to an effort to determine if the activation of non-canonical cytoprotective responses explain the differential response of oligodendrocytes to ER stress and inflammation. In aim 3 will examine the contribution of NRF2, which is phosphorylated by the stress-sensing kinase PERK, to these responses. In aim 4 we will examine a recently discovered ER stress response pathway that is triggered by the cell migration inducing hyaluronidase 2 (TMEM2), which is of potential relevance to myelinating and remyelinating oligodendrocytes. Together the work described in this proposal will significantly advance our understanding of the response of oligodendrocytes to various cytotoxic insults, which will provide important information critical to the development of neuroprotective therapies for oligodendrocytes and other cells of the nervous system.