Molecular Mechanisms of Oligodendrocyte Myelination and remyelination

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

Investigators

Abstract

Summary of Proposed Research Demyelinating diseases of the central nervous system, such as multiple sclerosis (MS), are among the most devastating and disabling neurological disorders that lead to severe handicaps and even death. Although substantial efforts have been made centered on the suppression of the immune response that attacks myelin, it is becoming clear that this approach does not address the major problem of the disease: the loss of myelin. A common feature in the demyelinated lesions is the blockage of myelin production by oligodendrocytes. Thus, the identification of critical factors that promote myelin production from oligodendrocytes and block inhibitory signals impeding myelination will help devise effective strategies for improving myelin repair in demyelinating diseases. Epigenetic reprogramming has been shown to rejuvenate cellular activity and thus is a promising approach to enhance repair capacity after injury. Our unprecedented screen using CNP+ oligodendrocytes identified epigenetic compounds that potently stimulate for myelin production and myelinogenesis. The top hit compound promotes remyelination in animal models of MS and initiates de novo myelination of regenerated axons after optic nerve crush. Our preliminary data suggest that the histone deacetylase HDAC3 is a target of the hit compound. Expression of HDAC3 is detected in oligodendrocytes that fail to produce myelin in human demyelinated MS lesions. Moreover, silencing of HDAC3 led to ectopic myelinogenesis in the developing brain and promoted robust remyelination after injury. Since the cellular specificity and function of HDACs are dependent on subunit compositions and interacting factors in multi- protein complexes, we further identified an HDAC3-interacting protein, the zinc-finger protein Znhit1, which is a key subunit of SNF2-related SRCAP chromatin-remodeling enzyme. Our preliminary data show that Znhit1 is enriched in oligodendrocytes and critical for oligodendrocyte myelination, while overexpression of Znhit1 promotes myelin gene expression. Based on these observations, we will utilize spatio-temporally specific mutagenesis approaches to identify the critical time window for the function of class I histone deacetylase isoforms in remyelination in animal models of MS and identify the HDAC3-Znhit1 regulatory network in myelination and remyelination. Furthermore, we will determine the therapeutic benefits of HDAC3 inhibitors for myelin repair. The proposed studies will advance our understanding of the mechanisms of central nervous system myelination and will also identify factors that could be targeted to promote oligodendrocyte regeneration and myelin repair in patients with demyelinating diseases such as MS, aging, leukodystrophies, stroke, autism, and injury to the brain or spinal cord.