Pex1 loss-of-function in zebrafish is viable and recapitulates hallmarks of Zellweger spectrum disorders
Bibliographic record
Abstract
Zellweger spectrum disorders (ZSDs) are rare autosomal recessive conditions belonging to the larger group of peroxisome biogenesis disorders. The most prevalent form of ZSD is caused by mutations in the PEX1 gene, which encodes an AAA ATPase protein. Cells lacking functional PEX1 fail to import proteins crucial for the formation of competent peroxisomes, resulting in aberrant structures called ghost peroxisomes . Peroxisome dysfunction leads to the accumulation of compounds that are normally metabolized in this compartment, including very long-chain fatty acids (VLCFAs), pristanic and phytanic acids, as well as deficiency in compounds that are normally formed in this organelle, including docosahexaenoic acid (DHA) and plasmalogen precursors. Patients with a complete lack of PEX1 function develop severe symptoms and have a poor prognosis, with death in the first year of life. In the absence of effective treatments for ZSD, advancing our understanding of this complex multisystem disorder remains essential for uncovering new therapeutic opportunities. To this end, we generated and characterized a zebrafish model with Pex1 loss-of-function. Surprisingly, despite the early onset of disease-relevant features, about 10% of pex1 –/– zebrafish reached adulthood. However, this resilience was short-lived, as none of the mutant fish survived beyond one year. Histopathological analysis of the liver in adult pex1 –/– mutants revealed a profound peroxisomal import deficiency and severe vacuolation. Moreover, key metabolic hallmarks of ZSDs, including accumulation of VLCFAs and methyl-branched fatty acids phytanic and pristanic acid, were consistently detected in larval and adult pex1 –/– mutants. Transcriptomics analysis in pex1 –/– larvae revealed upregulation of ER-stress responses and pexophagy, as well as dysregulation of neurophysiological processes and visual perception. The latter findings were corroborated by abnormal locomotor behavior in the larvae and by disrupted outer nuclear and retinal layer architecture in adult mutant animals. The described zebrafish pex1 model provides a versatile in vivo platform to uncover novel disease-relevant pathways in ZSD and to investigate the physiological impact of VLCFAs and methyl-branched fatty acids. Its relative tolerance to Pex1 loss-of-function circumvents the early lethality observed in mouse models, enabling the study of ZSD pathophysiology beyond early developmental stages and offering a valuable tool for preclinical therapeutic exploration.
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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 | 0.001 |
| 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".