The involvement of thioredoxin-1 in neuronal laminopathy in neurodegeneration
Bibliographic record
Abstract
Introduction: Progressive loss of neurons is a common cause in pathophysiology of neurodegenerative diseases (ND), although the underlying mechanisms responsible for cell death remains controversial. All ND are identified by accumulation of abnormal protein aggregates which have been traditionally targeted as the cause of neuronal loss in numerous experimental and clinical trials; however, there is currently no effective treatment available for these diseases. The involvement of oxidative stress in ND has also been well-documented by accumulation of oxidized proteins and declined antioxidant capacity of the nervous tissue. Thioredoxin-1 (Trx1) is one of these antioxidant proteins, responsible for regulating the redox status of cellular proteins. Lowered Trx1 level has been reported in the brain autopsy from Alzheimer’s disease (AD) patients, however, the cause and the consequence remain mostly unknown. Our lab has identified that loss of Trx1 is an important upstream event in induction of nuclear lamina (NL) invagination in neurons, known as laminopathy. This is a newly identified mechanism in pathophysiology of ND and has been linked to epigenetic changes and aberrant gene expression. Therefore, understanding the underlaying mechanisms in nuclear laminopathy may reveal new information about these diseases. Hypothesis: Decreased anti-oxidative capacity due to Trx1 downregulation is sufficient to induce nuclear lamina damage and reorganize chromatin structure, which leads to downstream aberrant gene expression that cause neuronal death. Methods: I used RNA interfering technology to downregulate Trx1 protein in human neuroblastoma cells (SH-SY5Y) and rat primary cortical neurons. I then used real-time PCR, western blotting, immunocytochemistry, and pyrosequencing to examine the structural and molecular nuclear events after Trx1 downregulation. Results: Genetic downregulation of Trx1 in SH-SY5Y cells was sufficient for induction of caspase-6 and NL damage. Moreover, I detected robust changes in cytoskeleton that was mediated by increased levels of F-actin fibrilization and were associated with laminopathy. These effects were also recapitulated in Trx1-depleted rat primary neurons. Activation of FoxO3a, as a cellular stress sensor, was shown by its phosphorylation status and the increased expression of its target proteins. Furthermore, accumulation of Double strand break (DSB) DNA damage and a significant increase in DNA methylating enzymes DNMT1 and DNMT3b was detected. Methylation status of repetitive elements in genome such as LINE-1 represents the overall DNA methylation level. However, my experiments did not show if Trx1 ablation changes LINE-1 methylation. This was despite histone modifications and aberrant transposable gene expression. These adverse effects were partially rescued, and cell viability was improved by administration of Thioredoxin mimetic peptide (CB3). Conclusion: This study provides a mechanistic link between Trx1 downregulation and induction of nuclear and cytoskeleton changes which might contribute to the pathophysiology of ND. Identification of specific genes with altered DNA methylation and/or histone modification will help to design novel therapeutic target.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".