A novel noncoding RNA rescues mutant SOD1-mediated cell death.

Transgenic mice expressing mutant Cu2+/Zn2+ superoxide dismutase SOD1(G93A) develop similar clinical and pathological phenotypes to amyotrophic lateral sclerosis (ALS) patients. Here, we utilize representational difference analysis to identify the transcripts that are up-regulated in the presymptomatic stage of SOD1(G93A) mice. Unexpectedly, three predominant clones were 18S or 28S ribosomal RNA (rRNA) segments. One of these clones corresponded to a capped and polyadenylated transcript containing a large portion of 18S rRNA, named MSUR1 (mutant SOD1-up-regulated RNA 1). In vitro expression experiments show that MSUR1 is able to rescue SOD1(G93A)-mediated cell death. Expression of MSUR1 significantly reduces SOD1(G93A)-induced free radical levels and oxidative damage. Further, MSUR1 can reduce hydrogen peroxide-mediated cytotoxicity. MSUR1 does not encode a protein, suggesting its role as a functional noncoding RNA. It is widely expressed in various tissues. Searching the database of GenBank revealed that a large number of expressed sequence tag (EST) clones contain large portions of rRNA sequence, potentially indicating a heretofore overlooked class of mRNAs with functional significance.

The identification and characterization of oxidized RNAs in Alzheimer's disease.

It has been shown that cytoplasmic RNA oxidation occurs to a great extent in the brains of Alzheimer's disease (AD) patients. The goal of this study was to isolate and identify oxidized RNA species in AD. We show that significant amounts of poly(A)+ mRNAs are oxidized in AD brains. RNA oxidation is not random but highly selective. Importantly, many identified oxidized mRNA species have been implicated in the pathogenesis of AD. Quantitative analysis revealed that some mRNA species are more susceptible to oxidative damage. We also investigated the biological consequence of oxidatively damaged mRNAs by expressing them in cell lines. Our data indicated that abnormal processing of proteins occurred to the oxidized mRNAs. This may implicate the potential contribution of RNA oxidation in the pathogenesis of AD.

Clinical features and neuropathological findings of familial amyotrophic lateral sclerosis with a His46Arg mutation in Cu/Zn superoxide dismutase.

We examined the characteristic clinical features of one family of familial amyotrophic lateral sclerosis (FALS) with a His46Arg mutation in the enzyme Cu/Zn superoxide dismutase-1 (SOD1). The disease duration for this family was 18.1 +/- 13.2 (mean +/- S.D.) years, with the age at onset being 39.7 +/- 10.5 years old (mean +/- S.D.). The initial sign was distal weakness of the unilateral lower limb, extending to the lower limb of the other side. A wheel chair became necessary at 9.8 +/- 3.2 years after the onset. Upper limb weakness started at 15.5 +/- 8.9 years following from the onset. An autopsy was performed on a 71-year-old woman of the family with the mutation. Her disease duration was 47 years, and she died of pneumonia. She had no clear upper motor neuron involvement. Bulbar sign and respiratory muscle weakness had developed 2 years before her death. Neuropathological findings showed degeneration of corticospinal tracts, anterior/posterior spinocerebellar tracts, posterior columns, and Clarke's columns. There were few anterior horn cells in the lumbar spinal cord and no Lewy body-like hyaline inclusion bodies in these remaining anterior horn neurons. This is the first autopsy report of FALS with a His46Arg mutation in the SOD1 enzyme.

Effects of light intensity through resin inlays on the bond strength of dual-cured resin cement.

PURPOSE: To evaluate the influence of the light intensity, irradiation time, and thickness of the indirect restoration composite on the bond strength of dual-cured resin cement immediately after cementation, applying the resin coating technique. MATERIALS AND METHODS: Three hundred forty composite blocks as an adhesive surface and four thicknesses of indirect restoration composite disks were prepared. The surface of the composite blocks was coated with low-viscosity resin composite and immersed in water for 24 h. After immersion, dual-cured resin cement was applied to the resin-coated surface and the indirect restoration composite disks were placed on it. Light irradiation was performed through four thicknesses of indirect restoration composite disks with conventional halogen (40 s) and high intensity (10, 20, 40 s) light units. The specimens were stored in water at 37 degrees C for 10 min or 24 h, and the tensile bond test was performed. RESULTS: For the 1-mm composite thickness, there were no significant differences in the bond strengths between 10 min and 24 h after cementation with the four light curing methods. For the composite thicknesses of 3 or 4 mm, the bond strength 24 h after cementation was significantly higher than that at 10 min after cementation with conventional halogen (40 s) and high-intensity light units at 10 s and 20 s, but there was no significant difference with the high-intensity light unit applied for 40 s. CONCLUSION: The bond strength of dual-cured resin cement immediately after cementation could be greatly influenced by the irradiation time and the light intensity penetrating the indirect restoration composite.

RNA oxidation: a contributing factor or an epiphenomenon in the process of neurodegeneration.

In the past decade, RNA oxidation has caught the attention of many researchers, working to uncover its role in the pathogenesis of neurodegenerative diseases. It has been well documented that RNA oxidation is involved in a wide variety of neurological diseases and is an early event in the process of neurodegeneration. The analysis of oxidized RNA species revealed that at least messenger RNA (mRNA) and ribosomal RNA (rRNA) are damaged in several neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis (ALS). The magnitude of the RNA oxidation, at least in mRNA, is significantly high at the early stage of the disease. Oxidative damage to mRNA is not random but selective and many oxidized mRNAs are related to the pathogenesis of the disease. Several studies have suggested that oxidative modification of RNA affects the translational process and consequently produces less protein and/or defective protein. Furthermore, several proteins have been identified to be involved in handling of damaged RNA. Although a growing body of studies suggests that oxidative damage to RNA may be associated with neuron deterioration, further investigation and solid evidence are needed. In addition, further uncovering of the consequences and cellular handling of the oxidatively damaged RNA should be important focuses in this area and may provide significant insights into the pathogenesis of neurodegenerative diseases.

The presence of rRNA sequences in polyadenylated RNA and its potential functions.

Accumulating evidence has shown that various lengths of ribosomal RNA (rRNA) sequences are widely present in polyadenylated RNA. This review article will discuss these polyadenylated rRNA containing transcripts (PART). PART are highly abundant and widely expressed in various tissues. It appears that there may be two types of PART. One type, type I, contains the rRNA segments (from approximately 10 nucleotides up to several hundred nucleotides) located within the transcripts. It has been demonstrated that short rRNA sequences within type I PART may function as cis-regulatory elements that regulate translational efficiency. The other type, type II, contains large portions or almost entire sequences of rRNA with a cap at the 5' end and poly(A) at 3' end. Recent work has shown that some type II PART have functional significance for some neurodegenerative disease processes and may play an important role in the pathogenesis of diseases. Further investigation in this area is critical to understanding the basic biology of PART and the potential role of PART in diseases.