Axonal pathology in hPSC‐based models of Parkinson's Disease results from loss of Nrf2‐transcriptional activity at the Map1b gene locus
Bibliographic record
Abstract
Introduction Neurological dysfunction in Parkinson's Disease (PD) is highly associated with pathological deposits of aggregated α‐synulein (α‐syn) in neurons of the brain, and yet an understanding of how early α‐syn deposits bring about neuronal pathology remains elusive. While mutations in the SNCA gene (a‐syn) are causal in rare familial forms of PD, the prevalence of α‐syn aggregates in the cortices of sporadic disease cases emphasizes the need to understand the link between α‐syn accumulation and axonal neuropathology. Approach This study exploits recent advances in isogenic stem cell technology to model PD using human pluripotent stem cell (hPSC) models of the familial disease. By employing 1) a combination hPSCs that harbor the SNCA ‐A53T mutation contrasted against isogenic controls and 2) substantia nigra from PD patients analyzed post‐mortem, we performed gene expression profiling in search of transcriptional hubs that are disrupted early in disease pathogenesis and remain altered as the disease progresses. We then evaluated the relationship between differentially expressed genes and axonal pathology. Results We show that the early accumulation of α‐syn in SNCA ‐A53T hNs results in changes in gene expression consistent with the expression profile of substantia nigra from PD patients, analyzed post‐mortem. Differentially expressed genes from both PD‐patient substantia nigra and SNCA ‐A53T hNs clustered to genes with regulatory motifs transcriptionally activated by the antioxidant response pathway, particularly, Nrf2 gene targets. Differentially expressed gene targets were also enriched for gene ontologies related to microtubule binding processes. We thus assessed the relationship between Nrf2‐mediated gene expression and axonal pathology in SNCA ‐A53T hNs. Here, we provide direct evidence that axonal pathology in PD neurons results from impaired Nrf2‐activity on Antioxidant Response Elements (ARE) localized to a microtubule associated protein (Map1b) gene enhancer. Moreover, we show that forced activation of Map1B, rescues axonal pathology in PD neurons. Significance This is the first demonstration of Nrf2‐mediated modulation of cytoskeletal elements as a potential therapy against PD‐induced axonal pathology. Support or Funding Information This work was supported in part by the Parkinson Society of Canada (2014‐685 to SDR), the Natural Sciences and Engineering Research Council of Canada (RG060805 to SDR) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".