J-domain protein molecular chaperones in inherited cerebellar ataxia: cellular dysfunction and altered metabolism associated with loss of DNAJC29/sacsin and DNAJC3
Bibliographic record
Abstract
Proteins containing a J-domain, (known as DnaJ proteins) act to recruit the Hsp70 molecular chaperone machinery to multiple cellular processes. Mutations in several J-domain proteins cause neurological disorders, that are considered “chaperonopathies” as the molecular pathology is believed to be associated with loss of chaperone activity. This thesis focuses on two of these conditions that have cerebellar ataxia as a core component of their phenotype: Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), caused by mutations in the SACS gene, which encodes DNAJC29/sacsin; and an ataxia syndrome that also presents with early-onset diabetes mellitus, caused by mutations in DNAJC3. The overarching aim of this thesis was to better understand the cellular consequences of sacsin and DNAJC3 dysfunction, with a focus on metabolic pathways. The first part of the thesis investigated alterations in cellular metabolism in a neuronal cell model of ARSACS. This identified metabolic rewiring as a consequence of sacsin knockout and highlighted potential targets for therapeutic interventions, such as modulation of GABA neurotransmitter levels. Further investigation of the cellular phenotype associated with loss of sacsin, characterised disruption of the microtubule cytoskeleton and its regulators (e.g., tau), altered integrin trafficking and impaired focal adhesion dynamics. These aspects of the loss of sacsin phenotype were further investigated in the mouse retina, which was selected based on the presence of a retinal phenotype in ARSACS patients. In the final part of the thesis, a novel cellular model for DNAJC3 loss of function was developed. Molecular characterisations of this model were then performed by metabolomic and transcriptomic analysis. In summary, defining cellular deficits associated with the loss of sacsin and DNAJC3 is a valuable first step towards understanding molecular mechanism of disease and identification of potential therapeutic strategies for these ataxias. It also broadens our understanding of the cellular roles of J-domain proteins.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".