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1.
Cells ; 8(12)2019 11 23.
Article in English | MEDLINE | ID: mdl-31771229

ABSTRACT

Amyotrophic lateral sclerosis (ALS) caused by mutation of superoxide dismutase 1 (SOD1), affects various cellular processes and results in the death of motor neurons with fatal defects. Currently, several neurological disorders associated with DNA damage are known to directly induce neurodegenerative diseases. In this research, we found that cytoplasmic restriction of SOD1G93A, which inhibited the nucleic translocation of SOD1WT, was directly related to increasing DNA damage in SOD1- mutated ALS disease. Our study showed that nucleic transport of DNA repair- processing proteins, such as p53, APEX1, HDAC1, and ALS- linked FUS were interfered with under increased endoplasmic reticulum (ER) stress in the presence of SOD1G93A. During aging, the unsuccessful recognition and repair process of damaged DNA, due to the mislocalized DNA repair proteins might be closely associated with the enhanced susceptibility of DNA damage in SOD1- mutated neurons. In addition, the co-expression of protein disulphide isomerase (PDI) directly interacting with SOD1 protein in neurons enhances the nucleic transport of cytoplasmic- restricted SOD1G93A. Therefore, our results showed that enhanced DNA damage by SOD1 mutation-induced ALS disease and further suggested that PDI could be a strong candidate molecule to protect neuronal apoptosis by reducing DNA damage in ALS disease.


Subject(s)
Cytoplasm/metabolism , DNA Repair , Neurons/metabolism , Spinal Cord/metabolism , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism , Animals , Cells, Cultured , Female , Mice , Mice, Transgenic , Mutation , Neurons/cytology , Pregnancy , Spinal Cord/cytology
2.
Invest Ophthalmol Vis Sci ; 55(2): 993-1005, 2014 Feb 18.
Article in English | MEDLINE | ID: mdl-24458150

ABSTRACT

PURPOSE: To test whether a diet supplemented with coenzyme Q10 (CoQ10) ameliorates glutamate excitotoxicity and oxidative stress-mediated retinal ganglion cell (RGC) degeneration by preventing mitochondrial alterations in the retina of glaucomatous DBA/2J mice. METHODS: Preglaucomatous DBA/2J and age-matched control DBA/2J-Gpnmb(+) mice were fed with CoQ10 (1%) or a control diet daily for 6 months. The RGC survival and axon preservation were measured by Brn3a and neurofilament immunohistochemistry and by conventional transmission electron microscopy. Glial fibrillary acidic protein (GFAP), superoxide dismutase-2 (SOD2), heme oxygenase-1 (HO1), N-methyl-d-aspartate receptor (NR) 1 and 2A, and Bax and phosphorylated Bad (pBad) protein expression was measured by Western blot analysis. Apoptotic cell death was assessed by TUNEL staining. Mitochondrial DNA (mtDNA) content and mitochondrial transcription factor A (Tfam)/oxidative phosphorylation (OXPHOS) complex IV protein expression were measured by real-time PCR and Western blot analysis. RESULTS: Coenzyme Q10 promoted RGC survival by approximately 29% and preserved the axons in the optic nerve head (ONH), as well as inhibited astroglial activation by decreasing GFAP expression in the retina and ONH of glaucomatous DBA/2J mice. Intriguingly, CoQ10 significantly blocked the upregulation of NR1 and NR2A, as well as of SOD2 and HO1 protein expression in the retina of glaucomatous DBA/2J mice. In addition, CoQ10 significantly prevented apoptotic cell death by decreasing Bax protein expression or by increasing pBad protein expression. More importantly, CoQ10 preserved mtDNA content and Tfam/OXPHOS complex IV protein expression in the retina of glaucomatous DBA/2J mice. CONCLUSIONS: Our findings suggest that CoQ10 may be a promising therapeutic strategy for ameliorating glutamate excitotoxicity and oxidative stress in glaucomatous neurodegeneration.


Subject(s)
Disease Models, Animal , Glaucoma/drug therapy , Glutamic Acid/metabolism , Mitochondria/drug effects , Oxidative Stress/drug effects , Ubiquinone/analogs & derivatives , Vitamins/therapeutic use , Animals , Axons/drug effects , Axons/pathology , Blotting, Western , Female , Glaucoma/metabolism , Glial Fibrillary Acidic Protein , Heme Oxygenase-1/metabolism , In Situ Nick-End Labeling , Membrane Proteins/metabolism , Mice , Mice, Inbred DBA , Mitochondria/metabolism , Nerve Tissue Proteins/metabolism , Real-Time Polymerase Chain Reaction , Receptors, N-Methyl-D-Aspartate/metabolism , Retinal Degeneration/metabolism , Retinal Degeneration/pathology , Retinal Degeneration/prevention & control , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/pathology , Superoxide Dismutase/metabolism , Ubiquinone/administration & dosage , Ubiquinone/therapeutic use , Vitamins/administration & dosage , bcl-Associated Death Protein/metabolism
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