Role of misfolded SOD1 in neurodegenerative diseases
Bibliographic record
Abstract
Emerging studies provide substantial support for a role of oxidative stress in neurodegeneration. Superoxide dismutase 1 (SOD1), a widely expressed antioxidant, has been shown to be a target of oxidative stress in the brain. After being oxidized, SOD1 becomes misfolded and gains a toxic property to neuronal cells. The present study aims to understand the role of misfolded SOD1 in neurodegenerative disorders and consists of two parts: 1) To determine the efficacy and specificity of a peptide-directed chaperone-mediated autophagy in selective degradation of misfolded SOD1; and 2) To examine the role of misfolded SOD1 in the formation of amyloid plaques. SOD1 misfolding is regarded as the cause of amyotrophic lateral sclerosis (ALS). Therefore, knockdown of misfolded SOD1 is a potential therapeutic strategy for ALS In my project, I have designed a peptide-directed strategy to knockdown misfolded SOD1. The DCT4-CTM peptide specifically recognizes misfolded SOD1 and induces degradation of the misfolded SOD1 through the chaperone-mediated-autophagy (CMA) pathway. I demonstrated the efficacy of DCT4-CTM in misfolded SOD1 knockdown in multiple models including cell lines, primary cortical neuron and ALS mice. Based on my results, DCT4-CTM peptide-directed knockdown of misfolded SOD1 is an effective strategy to degrade misfolded SOD1. On the other hand, Aβ protein aggregation is widely observed in the pathogenesis of Alzheimer’s disease (AD) and considered as an initial step of the formation of amyloid plaques. The mechanism of Aβ aggregation remains to be revealed. Increasing studies suggest that oxidative stress is involved in the Aβ aggregation process. I hypothesize that misfolded SOD1 is a key factor in the aggregation of Aβ. Here I show that Aβ aggregation increased in cell-free incubation with misfolded SOD1 but not with wild type SOD1. In addition, expression of aggregated Aβ in mutant SOD1-transfected N2A/APPsw cells increased. In APP/G37R mice, intracellular Aβ aggregation was significantly increased. The results demonstrated that misfolded SOD1 promoted intracellular Aβ aggregation both in vitro and in vivo. Our data suggested that SOD1 misfolding may be one of the earliest events in AD.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".