Year: 2014
Type: dissertation
Abstract: Myelin basic protein (MBP) is essential for the formation of myelin in the central nervous system (CNS).We have examined three factors that can potentially regulate its expression posttranscriptionally: the fragile X mental retardation protein (FMRP), the fragile X premutation transcript, and the tumor overexpressed gene (TOG) protein.We have revealed the presence of FMRP, a known translation inhibitor, in oligodendrocytes (OLGs) but found it had no effect on the translation of MBP mRNA.Correspondingly, the absence of FMRP in the Fmr1 KO mouse did not result in increased MBP translation.The presence in FXTAS patients of the fragile X premutation transcript, which contains expanded CGG repeats, has been associated with myelin changes in the CNS.We have found expanded CGG repeat RNA to be present in RNA granules that contain MBP transcripts.The presence of expanded CGG repeat RNA increased the expression of MBP mRNA in OLGs.In addition, increased translation of microinjected MBP mRNA occurred in fibroblasts from FXTAS individuals, suggesting that MBP mRNA translation may be upregulated in FXTAS.Knocking out TOG in mouse OLGs results in the near absence of MBP, despite a normal level of MBP transcripts, and extensive CNS dysmyelination.Levels of other myelin proteins, proteolipid protein (PLP) and myelin-associated glycoprotein (MAG), were found to be similarly reduced.We have determined that TOG heterozygote (+/null) mice, which express half the normal level of TOG, have normal MBP levels before 45 days of age.This suggests that another mechanism, besides the originally proposed decrease in MBP mRNA translation, is the Anthony William Giampetruzzi -University of Connecticut, 2014cause of MBP deficiencies in the 90 day old TOG heterozygotes.TOG is a microtubuleassociated protein and may be necessary for the transport of MBP mRNA granules to the myelin compartment where translation occurs.The effect of the reduction of TOG on microtubule based transport was examined by measuring the transport parameters of mitochondria in the processes of cultured OLGs.The transport of mitochondria was only slightly altered in the TOG heterozygote.These results suggest that approximately half the amount of TOG allows for sufficient transport and proper translation of MBP mRNA.
Author: Anthony Giampetruzzi
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W41304035