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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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Some proteins corresponding to oxidized mRNA species are decreased.(A & B) immunofluorescent staining of lumbar spinal cord sections prepared from indicated mice (n = 3) showed that downregulation of protein levels in SOD1G93A mice was found in cytochrome c oxidase VIb (Cox VIb) and NADH-ubiquinol oxidoreductase subunit 39 kDa (NADH oxi), whose mRNAs were highly oxidized but not EAAT3 protein, whose mRNA was not oxidized. Statistic analysis of immunoreactivity within motor neurons (n = 20) is shown. *P<0.0001 (C) Immunoblot analysis showed that MBP, whose mRNA was oxidized, was decreased. Densitometry analysis (standardized by actin intensity) of immunoblot is shown (n = 3). #P<0.01.
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pone-0002849-g005: Some proteins corresponding to oxidized mRNA species are decreased.(A & B) immunofluorescent staining of lumbar spinal cord sections prepared from indicated mice (n = 3) showed that downregulation of protein levels in SOD1G93A mice was found in cytochrome c oxidase VIb (Cox VIb) and NADH-ubiquinol oxidoreductase subunit 39 kDa (NADH oxi), whose mRNAs were highly oxidized but not EAAT3 protein, whose mRNA was not oxidized. Statistic analysis of immunoreactivity within motor neurons (n = 20) is shown. *P<0.0001 (C) Immunoblot analysis showed that MBP, whose mRNA was oxidized, was decreased. Densitometry analysis (standardized by actin intensity) of immunoblot is shown (n = 3). #P<0.01.

Mentions: Our previous studies demonstrated that oxidative modification of mRNA causes reduced protein expression [11], [12]. We examined protein expression levels for the oxidized mRNA species. Since the oxidized mRNAs primarily occur in motor neurons, which are small portion of total spinal cord cell population, immunoblot analysis was not sensitive enough to detect the change, so immunofluorescent staining was performed. The results showed that some proteins, whose mRNAs were highly oxidized, were significantly decreased in the motor neurons of 60 day-old SOD1G93A lumber spinal cords, such as cytochrome c oxidase VIb (Fig. 5A, Cox VIb) and NADH-ubiquinol oxidoreductase subunit 39 kDa (Fig. 5B, NADH oxi). On the other hand, the neuronal glutamate transporter EAAT3, whose mRNA was not oxidized, was not decreased. Further, the white matter oligodendrocytes also showed significant mRNA oxidation in SOD1G93A mice (Fig. 2). MBP, whose mRNA was oxidized, was decreased as determined by immunoblotting (Fig. 5C). These results suggested that some proteins corresponding to oxidized mRNA species may be decreased.


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)

Some proteins corresponding to oxidized mRNA species are decreased.(A & B) immunofluorescent staining of lumbar spinal cord sections prepared from indicated mice (n = 3) showed that downregulation of protein levels in SOD1G93A mice was found in cytochrome c oxidase VIb (Cox VIb) and NADH-ubiquinol oxidoreductase subunit 39 kDa (NADH oxi), whose mRNAs were highly oxidized but not EAAT3 protein, whose mRNA was not oxidized. Statistic analysis of immunoreactivity within motor neurons (n = 20) is shown. *P<0.0001 (C) Immunoblot analysis showed that MBP, whose mRNA was oxidized, was decreased. Densitometry analysis (standardized by actin intensity) of immunoblot is shown (n = 3). #P<0.01.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2481395&req=5

pone-0002849-g005: Some proteins corresponding to oxidized mRNA species are decreased.(A & B) immunofluorescent staining of lumbar spinal cord sections prepared from indicated mice (n = 3) showed that downregulation of protein levels in SOD1G93A mice was found in cytochrome c oxidase VIb (Cox VIb) and NADH-ubiquinol oxidoreductase subunit 39 kDa (NADH oxi), whose mRNAs were highly oxidized but not EAAT3 protein, whose mRNA was not oxidized. Statistic analysis of immunoreactivity within motor neurons (n = 20) is shown. *P<0.0001 (C) Immunoblot analysis showed that MBP, whose mRNA was oxidized, was decreased. Densitometry analysis (standardized by actin intensity) of immunoblot is shown (n = 3). #P<0.01.
Mentions: Our previous studies demonstrated that oxidative modification of mRNA causes reduced protein expression [11], [12]. We examined protein expression levels for the oxidized mRNA species. Since the oxidized mRNAs primarily occur in motor neurons, which are small portion of total spinal cord cell population, immunoblot analysis was not sensitive enough to detect the change, so immunofluorescent staining was performed. The results showed that some proteins, whose mRNAs were highly oxidized, were significantly decreased in the motor neurons of 60 day-old SOD1G93A lumber spinal cords, such as cytochrome c oxidase VIb (Fig. 5A, Cox VIb) and NADH-ubiquinol oxidoreductase subunit 39 kDa (Fig. 5B, NADH oxi). On the other hand, the neuronal glutamate transporter EAAT3, whose mRNA was not oxidized, was not decreased. Further, the white matter oligodendrocytes also showed significant mRNA oxidation in SOD1G93A mice (Fig. 2). MBP, whose mRNA was oxidized, was decreased as determined by immunoblotting (Fig. 5C). These results suggested that some proteins corresponding to oxidized mRNA species may be decreased.

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