Molecular mechanisms underlying the pathogenesis of Leigh Syndrome French Canadian
Bibliographic record
Abstract
Functional mitochondria are required for cellular fitness and for generating ATP through oxidative phosphorylation (OXPHOS) pathway.Impaired mitochondrial function is associated with neurodegenerative disorders such as Leigh Syndrome French Canadian (LSFC), an earlyonset autosomal recessive disease common in a small northern region of Quebec, Saguenay Lac Saint Jean.The causative gene is located on chromosome 2 and encodes Leucine Rich Pentatricopeptide Repeat containing protein (LRPPRC), a Pentatricopeptide Repeat (PPR) protein localized in mitochondria.The exact function of LRPPRC remains to be elucidated, but in vivo studies have revealed that LRPPRC forms a complex with Steroid Receptor RNA activator stem loop interacting RNA binding protein (SLIRP), and this complex is required for mitochondrial mRNA stability.Biochemically, an LSFC subject carrying the founder missense mutation in LRPPRC (p.A354V) demonstrated a very heterogenous phenotype in different tissues.The work presented in this thesis first elaborates the impact of LRPPRC deficiency on mitochondrial function in liver-specific LRPPRC knock-out mice.We showed that the loss of LRPPRC caused a generalized growth delay and typical histological features of mitochondrial hepatopathy.At the molecular level, LRPPRC deficiency caused destabilization of a number of polyadenylated mitochondrial mRNAs and a severe complex IV and complex V (ATP synthase) assembly defect.The impact of LRPPRC deficiency was not limited to OXPHOS, but also included the impairment of long-chain fatty acid oxidation, a striking dysregulation of the mitochondrial permeability transition pore, and an alteration of trans-membrane H2O2 diffusion, which could result from the ATP synthase assembly defect and changes in the lipid composition of mitochondrial membranes.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 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".