Access Type

Open Access Thesis

Date of Award

January 2018

Degree Type

Thesis

Degree Name

M.S.

Department

Molecular Biology and Genetics

First Advisor

Robert P. Skoff

Abstract

Pelizaeus-Merzbacher disease (PMD) results from mutations in the proteolipid protein 1 (PLP1) gene including PLP1 duplications and deletions. The absence of PLP is preferable to PLP1/Plp1 duplication in PMD patients and rodents as lifespan of PLP1/Plp1 null mammals is nearly normal. The reason for this is not entirely understood. However, because of this, less attention has been placed on Plp1 null mutations than on classical PMD mutations. However, data show that PLP levels must be properly titrated to ensure normal brain function. Specifically, changes in PLP1/Plp1 expression can result in massive microglia activation in animal models of PMD and likely in human PMD patients. We asked if PLP plays a role in this activation and how. We hypothesized that PLP plays a necessary part in regulation of mitochondrial function and that a disturbance in PLP expression leads to an inflammatory response because of this. The purpose of this study was to investigate this hypothesis the Plp1ko mouse model as it has been studied previously in animals with excess PLP (Plp1tg mice). We found an extensive inflammatory response in Plp1ko as demonstrated by 2-3-fold increase in both the overall microglial cell number in both male and female mice at 1, 3, and 6 months in Plp1ko mice. This increase can be accounted for by a 3-fold increase in microglial proliferation throughout the white and grey matter of the cerebra. Activity of microglia was quantified based on branching patterns of cell processes and the expression of CD68 (a marker for activated microglia). An increase in activation in Plp1ko mice is observable as early as 1 month and continues to at least 6 months. Interestingly, morphology of microglia and the effects of inflammation in Plp1ko mice differs from Plp1tg mice. A decrease in pro-inflammatory cytokines, as well as an increase in arginase 1 expression in Plp1ko mice, leads us to believe that while Plp1ko mice do experience an inflammatory response, microglia reactivity could be neuroprotective due to an alternative, or M2, activation state. This anti-inflammatory response would help to explain the benefits of Plp1 deletion vs Plp1 duplication. This study of Plp1ko mice, along with previous studies of Plp1tg mice, uncovers a novel function of PLP: regulation of brain inflammation, most likely mediated by the increase or absence of PLP in the mitochondria of oligodendrocytes. This must be understood in greater detail if we are to understand therapies for PMD and other diseased states.

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