Proteasome Modulation for the Treatment of CDKL5 Deficiency Disorder
Bibliographic record
Abstract
CDKL5 Deficiency Disorder (CDD) is an X-linked neurodevelopmental disorder and epileptic encephalopathy caused by mutations in Cyclin-dependent kinase-like 5 (CDKL5). Numerous unique CDKL5 mutations have been identified, with the majority occurring within the region of the gene that encodes the kinase’s N-terminal catalytic domain. A subset of mutations has been identified in the region encoding the C-terminal domain of CDKL5, an area of the protein that is poorly understood. To better understand how C-terminal CDKL5 mutations result in CDD, we generated a novel, patient specific mouse model (Cdkl5del-CT) using Crispr-Cas9 targeted gene editing that houses the same 2-base pair deletion mutation identified in a Toronto-area CDD patient. Cdkl5del-CT mice demonstrate a number of biochemical, physiological, and behavioural phenotypes consistent with the clinical condition. It was discovered that the mechanism of pathogenesis in Cdkl5del-CT mice is through protein instability – distinct from the existing Cdkl5KO model. Efforts to increase Cdkl5 stability in Cdkl5del-CT mice led to the identification of proteasome inhibitors as a potential novel therapeutic strategy for CDD. The present experiments detail the biochemical and behavioural rescues found using proteasome inhibitors in Cdkl5del-CT mice. In summary, this thesis reports a distinct mechanism of CDD pathogenesis initiated by C-terminal mutations to Cdkl5 and identifies a novel therapeutic strategy that targets this underlying mechanism.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 0.001 |
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".