Investigation of two early events in amyotrophic lateral sclerosis -MRNA oxidation and up-regulation of a novel protective factor MSUR1-
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder that is characterized by progressive degeneration of motor neurons. Overexpression of some of ALS-linked mutant SOD1 proteins in transgenic mice results in the development of a neurological disorder that resembles ALS patients. This dissertation demonstrates two early events occurred in the pre-symptomatic stage of SOD1 (G93A) mice, including RNA oxidation and up-regulation of a novel protective factor MSUR1.The first part of this dissertation is to investigate the relationship between mRNA oxidation and motor neuron degeneration in SOD1 (G93A) mice. It was discovered that mRNA oxidation is an early event far preceding motor neuron degeneration, not merely a consequence of dying cells, and primarily occurs in motor neurons and oligodendrocytes that die later. Identification of oxidized mRNA species revealed that some mRNA species are more vulnerable to oxidative damage, and importantly, many oxidized mRNA species have been implicated in the pathogenesis of ALS. The expression level of protein corresponding to the oxidized mRNA species is significantly decreased. Furthermore, vitamin E can reduce mRNA oxidation and partially protect motor neurons from neurodegeneration in mice. Increased mRNA oxidation also occurs in the pre-symptomatic stage of other mutant SOD1 mice. Furthermore, mRNAs are oxidatively damaged in the affected areas of ALS. The phenomena of mRNA oxidation appear to be similar to the symptomatic stage of SOD1 (G93A) mice, suggesting that mRNA oxidation may be a common early event preceding motor neuron degeneration in ALS. The second part of this dissertation is to investigate a novel transcript named MSUR1, which is upregulated in the pre-symptomatic stage of SOD1 (G93A) mice. MSUR1 is an unusual RNA. It has a typical mRNA structure with a cap at the 5Œ end and poly(A) at 3Œ end, but is, essentially, a portion of 18S ribosomal RNA (rRNA). It was discovered that MSUR1 is able to rescue SOD1 (G93A)-mediated cell death in cultured cells. Expression of MSUR1 significantly reduced SOD1 (G93A)-induced free radical level and oxidative damage. MSUR1 does not encode a protein, suggesting a functional non-coding RNA. It was widely expressed in various tissues.
School:The Ohio State University
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:rna oxidation amyotrophic lateral sclerosis sod1 g93a neurodegeneration
Date of Publication:01/01/2007