Nuclear Localization of Human SOD1 in Motor Neurons in Mouse Model and Patient Amyotrophic Lateral Sclerosis: Possible Links to Cholinergic Phenotype, NADPH Oxidase, Oxidative Stress, and DNA Damage
Abstract
:1. Introduction
2. Results
2.1. hSOD1 Nuclear Localization in Tg Mouse Spinal Cord Is Cell-Type Differential and Disease-Related
2.2. Subcellular Fractionation of Brain and Spinal Cord of hSOD1-G93A Mice Shows Differential Enrichment of hSOD1 in Nuclear Chromatin Extracts
2.3. Isolation of an Intact Nuclear Fraction of Spinal Cord for Acute Live-Nucleus Analyses of Oxidative Stress and DNA Damage
2.4. MNs from Spinal Cord of Tg Mice Have hSOD1 Variant-Related Accumulation of DNA Single-Strand Breaks
2.5. NADPH Oxidase Has a Role in Disease in hSOD1-G93A Mice
2.6. SOD1 Localizes the Nucleus in MNs and Glia in Human CNS: Nuclear Presence Increases in ALS Upper and Lower MNs
2.7. Nuclear SOD1 Is Present in Human iPS Cells at Different Stages of Directed Differentiation to MNs, but Familial Mutant SOD1 ALS MNs Have Aberrant Subcellular Compartmentation of SOD1
3. Discussion
3.1. hSOD1-G93A MNs with Nuclear SOD1 Lose Their Cholinergic Phenotype of the Nucleus
3.2. Spinal Cord Oligodendrocytes in hSOD1-G93A Mice Adopt a Nuclear hSOD1 Phenotype during Disease
3.3. Oxidative Stress within the Nucleus and DNA Damage Occur in MNs in hSOD1-G93A Mouse Spinal Cord
3.4. NADPH Oxidase Is Involved in the Disease Process in hSOD1-G93A Mice
3.5. SOD1 Localizes to the Nucleus of MNs in Human ALS Brains and Spinal Cords and in Patient iPS Cell-Derived MNs in Cell Culture
4. Materials and Methods
4.1. Tg Mice
4.2. Immunohistochemistry on Mouse Spinal Cord
4.3. Preparation of Spinal Cord Tissue for Isolation of MNs and Cell Nuclei
4.4. Preparation of MN-Enriched Cell Suspensions and MN Nuclei
4.5. Preparation of Brain and Spinal Cord Subcellular Fractions
4.6. Immunoblotting
4.7. Comet Assay
4.8. NCF1 Gene Knockout Experiment
4.9. Pharmacological Intervention Experiment with Apocynin
4.10. Human Tissues
4.11. Human iPS Cells and Directed Differentiation
4.12. Quantitative and Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Group | Case Number | Age (Years)/Sex | Postmortem Delay (Hours) | Cause of Death |
---|---|---|---|---|
Controls (Neurological Disease Free) | 487 | 73/male | 22 | Pancreatic cancer |
515 | 62/male | 21 | Aortic aneurysm | |
712 | 44/female | 20 | Pneumonia | |
719 | 66/male | 10 | Myocardial infarction | |
961 | 59/female | 6 | Myocardial infarction | |
993 | 66/male | 12 | Prostatic carcinoma | |
1277 | 80/female | 8 | Lymphoma | |
1344 | 53/male | 12 | Metastatic carcinoma | |
1348 | 44/male | 18 | Lymphoma | |
1361 | 49/female | 15 | Thromboembolic disease | |
1517 | 71/female | 16 | Heart disease | |
1591 | 94/male | 16 | Pneumonia | |
1603 | 89/male | 16 | Pulmonary embolism | |
1613 | 74/male | 4 | Myocardial infarction | |
1683 | 91/female | 8 | Cardiomyopathy | |
ALS | 345 | 59/female | 3 | Respiratory arrest |
414 | 65/male | 4 | Respiratory arrest | |
433 | 71/male | 17 | Respiratory arrest | |
447 | 69/female | 15 | Respiratory arrest | |
492 | 68/female | 18 | Respiratory arrest | |
834F | 46/male | 3 | Respiratory arrest | |
875 | 70/female | 24 | Respiratory arrest | |
950F | 38/male | 22 | Respiratory arrest | |
1014 | 72/male | 5 | Respiratory arrest | |
1088 | 66/male | 7 | Respiratory arrest | |
1108 | 64/female | 8 | Respiratory arrest | |
1151 | 57/female | 14 | Respiratory arrest | |
1161 | 47/male | 6 | Pneumonia | |
1169 | 67/female | 15 | Respiratory arrest | |
1176F | 27/male | 6 | Respiratory arrest | |
1359 | 61/female | 14 | Respiratory arrest | |
1365 | 59/male | 7 | Respiratory arrest | |
1386 | 69/female | 15 | Pneumonia | |
1413 | 79/male | 10 | Respiratory arrest | |
1452 | 65/female | 6 | Respiratory arrest | |
1453 | 60/male | 22 | Pneumonia | |
1485 | 61/female | 5 | Pneumonia | |
1589 | 55/male | 10 | Pneumonia | |
1614 | 69/male | 18 | Respiratory arrest | |
1620 | 63/male | 10 | Respiratory arrest | |
1623 | 71/female | 59 | Cardiopulmonary arrest | |
1629 | 55/female | 12 | Pneumonia | |
1635 | 68/female | 5 | Respiratory arrest | |
1668 | 76/male | 7 | Respiratory arrest | |
1693F | 42/male | 6 | Respiratory arrest | |
1713 | 54/female | 14 | Respiratory arrest | |
1742 | 55/male | 5 | Pneumonia | |
1755 | 72/female | 5 | Respiratory arrest | |
1789F-SOD1A4V | 55/male | 14 | Respiratory arrest |
iPSC Lines (Clone) 1 | Gene | Mutation | Age of Donor | Gender |
---|---|---|---|---|
C3-1 | Control | N/A | 40 | F |
C3-1 | SOD1 | G93A | 40 | F |
GO013 | SOD1 | A4V | 63 | F |
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Martin, L.J.; Koh, S.J.; Price, A.; Park, D.; Kim, B.W. Nuclear Localization of Human SOD1 in Motor Neurons in Mouse Model and Patient Amyotrophic Lateral Sclerosis: Possible Links to Cholinergic Phenotype, NADPH Oxidase, Oxidative Stress, and DNA Damage. Int. J. Mol. Sci. 2024, 25, 9106. https://doi.org/10.3390/ijms25169106
Martin LJ, Koh SJ, Price A, Park D, Kim BW. Nuclear Localization of Human SOD1 in Motor Neurons in Mouse Model and Patient Amyotrophic Lateral Sclerosis: Possible Links to Cholinergic Phenotype, NADPH Oxidase, Oxidative Stress, and DNA Damage. International Journal of Molecular Sciences. 2024; 25(16):9106. https://doi.org/10.3390/ijms25169106
Chicago/Turabian StyleMartin, Lee J., Shannon J. Koh, Antionette Price, Dongseok Park, and Byung Woo Kim. 2024. "Nuclear Localization of Human SOD1 in Motor Neurons in Mouse Model and Patient Amyotrophic Lateral Sclerosis: Possible Links to Cholinergic Phenotype, NADPH Oxidase, Oxidative Stress, and DNA Damage" International Journal of Molecular Sciences 25, no. 16: 9106. https://doi.org/10.3390/ijms25169106