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


RESULTS
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.


CONCLUSIONS
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.
Chang
Yueming
Y
Department of Neuroscience, The Ohio State University, Columbus, Ohio, United States of America.
Kong
Qiongman
Q
Shan
Xiu
X
Tian
Guilian
G
Ilieva
Hristelina
H
Cleveland
Don W
DW
Rothstein
Jeffrey D
JD
Borchelt
David R
DR
Wong
Philip C
PC
Lin
Chien-Liang Glenn
CL
D000818:Animals; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009044:Motor Cortex / Q000378:metabolism; D016472:Motor Neuron Disease / Q000235:genetics* / Q000378:metabolism; D009410:Nerve Degeneration; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
D012333:RNA, Messenger; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1