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Messenger RNA oxidation occurs early in disease pathogenesis and promotes motor neuron degeneration in ALS.

Chang Y, Kong Q, Shan X, Tian G, Ilieva H, Cleveland DW, Rothstein JD, Borchelt DR, Wong PC, Lin CL - PLoS ONE (2008)

Bottom Line: Identification of oxidized mRNA species revealed that some species are more vulnerable to oxidative damage, and importantly, many oxidized mRNA species have been implicated in the pathogenesis of ALS.Oxidative modification of mRNA causes reduced protein expression.Reduced mRNA oxidation by vitamin E restores protein expression and partially protects motor neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, The Ohio State University, Columbus, Ohio, United States of America.

ABSTRACT

Background: Accumulating evidence indicates that RNA oxidation is involved in a wide variety of neurological diseases and may be associated with neuronal deterioration during the process of neurodegeneration. However, previous studies were done in postmortem tissues or cultured neurons. Here, we used transgenic mice to demonstrate the role of RNA oxidation in the process of neurodegeneration.

Methodology/principal findings: We demonstrated that messenger RNA (mRNA) oxidation is a common feature in amyotrophic lateral sclerosis (ALS) patients as well as in many different transgenic mice expressing familial ALS-linked mutant copper-zinc superoxide dismutase (SOD1). In mutant SOD1 mice, increased mRNA oxidation primarily occurs in the motor neurons and oligodendrocytes of the spinal cord at an early, pre-symptomatic stage. Identification of oxidized mRNA species revealed that some species are more vulnerable to oxidative damage, and importantly, many oxidized mRNA species have been implicated in the pathogenesis of ALS. Oxidative modification of mRNA causes reduced protein expression. Reduced mRNA oxidation by vitamin E restores protein expression and partially protects motor neurons.

Conclusion/significance: These findings suggest that mRNA oxidation is an early event associated with motor neuron deterioration in ALS, and may be also a common early event preceding neuron degeneration in other neurological diseases.

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Related in: MedlinePlus

Effect of vitamin E on the course of disease in SOD1G93A mice.(A) Cresyl violet-stained and toluidine blue-stained sections through the ventral horn of lumbar spinal cord showed partial preservation of neurons in vitamin E treated mice compared with non-treated mice at age of 100 days. The number of motor neurons in the lumbar spinal cord was counted (n = 3 per group, *P<0.01). Vitamin E delays the progressive loss of motor neurons. (B) Immunofluorescent staining of lumbar spinal cord sections showed that gliosis (GFAP staining) and ubiquitin aggregation (ubiquitin staining) were significantly reduced in vitamin E treated mice (100 day-old). The ventral horn area is shown. Scale bar, 10 µm. (C) Electron microscopy shows that vitamin E significantly reduces mitochondria vacuolization in motor neurons. Scale bar, 0.5 µm.
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pone-0002849-g007: Effect of vitamin E on the course of disease in SOD1G93A mice.(A) Cresyl violet-stained and toluidine blue-stained sections through the ventral horn of lumbar spinal cord showed partial preservation of neurons in vitamin E treated mice compared with non-treated mice at age of 100 days. The number of motor neurons in the lumbar spinal cord was counted (n = 3 per group, *P<0.01). Vitamin E delays the progressive loss of motor neurons. (B) Immunofluorescent staining of lumbar spinal cord sections showed that gliosis (GFAP staining) and ubiquitin aggregation (ubiquitin staining) were significantly reduced in vitamin E treated mice (100 day-old). The ventral horn area is shown. Scale bar, 10 µm. (C) Electron microscopy shows that vitamin E significantly reduces mitochondria vacuolization in motor neurons. Scale bar, 0.5 µm.

Mentions: One striking observation in the above onset study (Fig. 6) was that at the age of 100 days, the non-treated mice exhibited grip strength deficit and were sick while the treated mice still had normal motor performance and remained active. However, between 110 and 120 days of age, the treated mice developed onset rapidly and died within a similar age range as the non-treated mice. We therefore decided to examine the pathological changes at 100 days and 120 days of age. To examine the numbers and morphology of the motor neurons, we performed cresol violet staining on the lumbar spinal cord sections from non-treated and treated mice (n = 3 per group). The results showed that at 100 days of age, numerous of motor neurons were lost in the non-treated mice, and the remaining motor neurons were atrophic. In contrast, there was less motor neuron loss in sections from the treated mice, and the motor neurons were healthier in appearance, compared to the non-treated mice (Fig. 7A). However, at 120 days of age, there was no obvious difference between treated and non-treated mice samples, in that the majority of motor neurons had degenerated (not shown). We also performed toluidine blue staining (Fig. 7B), and the results were consistent with the cresol violet staining results. Importantly, there was significant vacuolization in the non-treated mice and only a slight vacuolization in the treated mice at 100 days of age. These results clearly indicated that vitamin E can reduce mRNA oxidation, restore protein expression level and partially protect motor neurons up to 100 days of age. Notably, significant protein oxidation [25], lipid peroxidation [26] and DNA oxidation [27] occurs at active disease progression stage; thus, the observed protective effects by vitamin E are primarily due to reduction of RNA oxidation.


Messenger RNA oxidation occurs early in disease pathogenesis and promotes motor neuron degeneration in ALS.

Chang Y, Kong Q, Shan X, Tian G, Ilieva H, Cleveland DW, Rothstein JD, Borchelt DR, Wong PC, Lin CL - PLoS ONE (2008)

Effect of vitamin E on the course of disease in SOD1G93A mice.(A) Cresyl violet-stained and toluidine blue-stained sections through the ventral horn of lumbar spinal cord showed partial preservation of neurons in vitamin E treated mice compared with non-treated mice at age of 100 days. The number of motor neurons in the lumbar spinal cord was counted (n = 3 per group, *P<0.01). Vitamin E delays the progressive loss of motor neurons. (B) Immunofluorescent staining of lumbar spinal cord sections showed that gliosis (GFAP staining) and ubiquitin aggregation (ubiquitin staining) were significantly reduced in vitamin E treated mice (100 day-old). The ventral horn area is shown. Scale bar, 10 µm. (C) Electron microscopy shows that vitamin E significantly reduces mitochondria vacuolization in motor neurons. Scale bar, 0.5 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2481395&req=5

pone-0002849-g007: Effect of vitamin E on the course of disease in SOD1G93A mice.(A) Cresyl violet-stained and toluidine blue-stained sections through the ventral horn of lumbar spinal cord showed partial preservation of neurons in vitamin E treated mice compared with non-treated mice at age of 100 days. The number of motor neurons in the lumbar spinal cord was counted (n = 3 per group, *P<0.01). Vitamin E delays the progressive loss of motor neurons. (B) Immunofluorescent staining of lumbar spinal cord sections showed that gliosis (GFAP staining) and ubiquitin aggregation (ubiquitin staining) were significantly reduced in vitamin E treated mice (100 day-old). The ventral horn area is shown. Scale bar, 10 µm. (C) Electron microscopy shows that vitamin E significantly reduces mitochondria vacuolization in motor neurons. Scale bar, 0.5 µm.
Mentions: One striking observation in the above onset study (Fig. 6) was that at the age of 100 days, the non-treated mice exhibited grip strength deficit and were sick while the treated mice still had normal motor performance and remained active. However, between 110 and 120 days of age, the treated mice developed onset rapidly and died within a similar age range as the non-treated mice. We therefore decided to examine the pathological changes at 100 days and 120 days of age. To examine the numbers and morphology of the motor neurons, we performed cresol violet staining on the lumbar spinal cord sections from non-treated and treated mice (n = 3 per group). The results showed that at 100 days of age, numerous of motor neurons were lost in the non-treated mice, and the remaining motor neurons were atrophic. In contrast, there was less motor neuron loss in sections from the treated mice, and the motor neurons were healthier in appearance, compared to the non-treated mice (Fig. 7A). However, at 120 days of age, there was no obvious difference between treated and non-treated mice samples, in that the majority of motor neurons had degenerated (not shown). We also performed toluidine blue staining (Fig. 7B), and the results were consistent with the cresol violet staining results. Importantly, there was significant vacuolization in the non-treated mice and only a slight vacuolization in the treated mice at 100 days of age. These results clearly indicated that vitamin E can reduce mRNA oxidation, restore protein expression level and partially protect motor neurons up to 100 days of age. Notably, significant protein oxidation [25], lipid peroxidation [26] and DNA oxidation [27] occurs at active disease progression stage; thus, the observed protective effects by vitamin E are primarily due to reduction of RNA oxidation.

Bottom Line: Identification of oxidized mRNA species revealed that some species are more vulnerable to oxidative damage, and importantly, many oxidized mRNA species have been implicated in the pathogenesis of ALS.Oxidative modification of mRNA causes reduced protein expression.Reduced mRNA oxidation by vitamin E restores protein expression and partially protects motor neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, The Ohio State University, Columbus, Ohio, United States of America.

ABSTRACT

Background: Accumulating evidence indicates that RNA oxidation is involved in a wide variety of neurological diseases and may be associated with neuronal deterioration during the process of neurodegeneration. However, previous studies were done in postmortem tissues or cultured neurons. Here, we used transgenic mice to demonstrate the role of RNA oxidation in the process of neurodegeneration.

Methodology/principal findings: We demonstrated that messenger RNA (mRNA) oxidation is a common feature in amyotrophic lateral sclerosis (ALS) patients as well as in many different transgenic mice expressing familial ALS-linked mutant copper-zinc superoxide dismutase (SOD1). In mutant SOD1 mice, increased mRNA oxidation primarily occurs in the motor neurons and oligodendrocytes of the spinal cord at an early, pre-symptomatic stage. Identification of oxidized mRNA species revealed that some species are more vulnerable to oxidative damage, and importantly, many oxidized mRNA species have been implicated in the pathogenesis of ALS. Oxidative modification of mRNA causes reduced protein expression. Reduced mRNA oxidation by vitamin E restores protein expression and partially protects motor neurons.

Conclusion/significance: These findings suggest that mRNA oxidation is an early event associated with motor neuron deterioration in ALS, and may be also a common early event preceding neuron degeneration in other neurological diseases.

Show MeSH
Related in: MedlinePlus