Characterization of <i>Dnajc12</i> knock-out mice, a model of hypodopaminergia
Bibliographic record
Abstract
Homozygous DNAJC12 c.79-2A>G (p. V27Wfs*14) loss-of-function mutations were first reported as a cause of young-onset Parkinson's disease. However, bi-allelic autosomal recessive pathogenic variants in DNAJC12 may lead to an alternative constellation of neurological features, including infantile dystonia, developmental delay, intellectual disability and neuropsychiatric disorders. DNAJC12 is understood to co-chaperone aromatic amino acid hydroxylases to foster the synthesis of biogenic amines. In vitro, we discover overexpressed DNAJC12 forms a complex with guanine triphosphate cyclohydrolase 1 (GCH1), the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, a cofactor paramount for biogenic amines synthesis. We also confirm DNAJC12's interaction with tyrosine (TH) and tryptophan hydroxylase (TPH), which are rate-limiting enzymes for synthesis of biogenic amines dopamine (DA) and serotonin (5-HT). In-vitro knock-down of DNAJC12 with a siRNA destabilizes the DNAJC12-TH-GCH1 complex, reducing GCH1 levels, whereas reciprocal overexpression of both TH and GCH1 increases endogenous DNAJC12, alluding to the significance of modulating the DNAJC12-TH-GCH1 complex as a therapy for DNAJC12 and other biogenic amine disorders. We extend these investigations to a Cre-conditional knock-out mice (cDKO) in which loxP sites flanking Dnajc12 exon 2 enable its excision by cre-recombinase. With germline Cre expression, we have created a constitutive Dnajc12 knock-out (DKO). DKO mice exhibit reduced locomotion/ exploratory behavior at 3 months in automated open-field testing, accompanied by increased plasma phenylalanine which is a cardinal feature of patients with pathogenic DNAJC12 variants. In striatal tissue, total DA and 5-HT, their metabolites, and electrically-evoked DA release are all reduced. Biochemical alterations in synaptic proteins are also apparent, with enhanced phosphorylation of Th pSer31 and pSer40 reflecting biological compensation. Most immediately, cDKO and DKO mice present models to develop and refine therapeutic approaches for biogenic amines disorders, including dystonia and parkinsonism. They will also enable the pleiotropic functions of biogenic amines (including DA), usually synthesized in the brain or periphery, to be separated.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".