Functional regulation of Sirt2 during oligodendrocyte development and its requirement during myelination and in an EAE mouse model of multiple sclerosis
Date
2019-03-11Author
Thangaraj, Merlin Premalatha 1986-
Type
ThesisDegree Level
DoctoralMetadata
Show full item recordAbstract
In the central nervous system (CNS), oligodendroglial cells (OLs) form the myelin that ensheaths axons to ensure fast, efficient neurotransmission. Multiple sclerosis (MS) is a chronic demyelinating disease where myelin and myelinating OLs are damaged, making the axons more susceptible to degeneration. The cellular and molecular mechanisms that control the myelinating ability of OLs are largely unknown. The RNA binding protein quaking (QKI) regulates the expression of several myelin specific genes. Sirtuin 2 (SIRT2) is a NAD+ dependent deacetylase predominantly expressed in OLs. Both qkI and Sirt2 are upregulated during the period of intense CNS myelination in vivo; however, it is not known whether these two genes interact to regulate OL differentiation. In the first study, I tested the hypothesis that QKI interacts with Sirt2 mRNA to promote the expression of SIRT2 in OLs during development. I report for the first time that QKI directly interacts with Sirt2 mRNA at the 3' untranslated region, protects Sirt2 mRNA from degradation, and promotes SIRT2 expression in OL lineage cells.
Considering the importance of Sirt2 in OL differentiation in vitro, I hypothesized that loss of Sirt2 would result in hypomyelination and increase the disease severity in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. My findings demonstrate that the loss of Sirt2 results in reduced expression of key myelin genes and a significant reduction in the number of myelinated axons in the CNS in vivo. In addition, Sirt2-/- mice displayed defects in OL precursor cells (OPC) proliferation and OL differentiation. EAE induction demonstrated that absence of Sirt2 results in an increased severity of EAE in Sirt2-/- mice compared to wild-type mice. These results suggest that Sirt2 plays a crucial role in OL development and myelination and a protective role in the EAE mouse model of MS. Finally, I investigated the targets through which Sirt2 could possibly regulate myelination. Cholesterol is crucial for myelin biogenesis. In neurons, SIRT2 has been implicated in cholesterol biosynthesis by promoting the nuclear translocation of SREBP-2. In this study, I hypothesized that SIRT2 positively regulates the translocation of SREBP-2 into the nucleus in OLs to promote cholesterol biosynthesis. My findings reveal that SREBP-2 and the downstream sterol biosynthesis pathway is not regulated by SIRT2 in OLs during CNS myelination.
Collectively, these findings suggest that QKI regulates the expression of Sirt2, which plays a critical role in oligodendrogenesis and myelination of axons in the CNS through SREBP-2/cholesterol-independent mechanism. In addition, Sirt2 plays a protective role in the EAE mouse model. I believe this research will advance our knowledge in identifying target molecules that regulate the myelinating ability of OLs, leading to the development of potential nutrient and pharmacological therapies for MS.
Degree
Doctor of Philosophy (Ph.D.)Department
Pharmacy and NutritionProgram
PharmacySupervisor
Alcorn, Jane; Popescu, Bogdan FCommittee
Badea, Ildiko; Popescu, Bogdan F; Harkness, Troy; Mousseau, Darrell D; Paterson, PhyllisCopyright Date
January 2019Subject
Sirt2, oligodendrocyte development, myelination and multiple sclerosis