Characterizing the role of mitochondrial dysfunction in Autosomal Recessive Spastic Ataxia of Charlevoix- Saguenay (ARSACS)
Bibliographic record
Abstract
Autosomal Recessive Cerebellar Ataxia of Charlevoix-Saguenay (ARSACS) is a complex inherited neurodegenerative disorder. First described in Quebec in 1978, ARSACS is caused by mutations in the SACS gene that encodes the giant protein of 4579 amino acids, Sacsin. Sacsin has been localized to mitochondria and the cytoplasm, but its function is unknown, and as a result the pathological mechanisms of this complex disease are currently poorly understood. Two features of ARSACS are intermediate filament bundles and elongated mitochondria. The purpose of this project was to evaluate mitochondrial function and to test the hypothesis that mitochondrial abnormalities in ARSACS are a downstream consequence of disordered intermediate filaments. To this end, two cellular models were used: motor neurons in Sacs-/- mouse-derived spinal cord-dorsal root ganglion (DRG) cultures and cultured skin fibroblasts derived from patients. Neurofilament bundling and a modest, but statistically significant, increase in length of mitochondria in motor neuron dendrites were observed after three weeks in vitro. This increase in mitochondrial length was more evident in fibroblasts cultured from ARSACS patients. Human fibroblasts also demonstrated similar bundling of vimentin intermediate filaments, validating the relevance of this model to the neuronal phenotype. With regard to interrogation of mitochondrial function, BN-PAGE of fibroblast mitochondria determined no difference in respiratory chain complex abundance or assembly, and bromouridine incorporation demonstrated no significant change in localization of newly synthesized mitochondrial RNA to RNA granules. Additionally, this study evaluated an intermediate filament-related phenotype that encompasses proteins involved in anchoring of the cytoskeleton to the nucleus (nesprin), consistent with displacement of organelles caused by bundling of intermediate filaments. Finally, to further examine the relationship between intermediate filament and mitochondrial phenotypes in ARSACS, these parameters were measured in fibroblasts from patients with Giant Axonal Neuropathy, a generalized disorder of intermediate filament organization. While intermediate filament bundling and displacement of nesprin and endoplasmic reticulum were found in both ARSACS and GAN fibroblasts, the latter cell line exhibited no change in mitochondrial length. This study provides evidence that changes in mitochondrial morphology observed in ARSACS are not a direct secondary effect that arises from the collapse of the intermediate filament network.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".