The involvement of thioredoxin-1 in neuronal laminopathy in neurodegeneration
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».