Characterization of a R493X progranulin haploinsufficient knockin mouse model of frontotemporal dementia
Bibliographic record
Abstract
Abstract Background Frontotemporal dementia (FTD) is the second most common form of dementia in young individuals, characterized by impairments in social cognition, language processing and executive function. Heterozygous loss‐of‐function mutations in the progranulin gene (GRN) are well known as a major genetic cause of a TDP‐43‐positive subtype of FTD (FTD‐GRN). The role of progranulin in the pathogenesis of FTD is not fully understood but has been shown to be associated with lysosomal dysfunction, impaired neuronal survival, and neuroinflammation. Rodent models of FTD‐GRN have been extensively used to model disease pathophysiology, but most studies utilize mice null for GRN. Our lab recently published a comprehensive neuropathological and behavioural assessment of a GRN R493X homozygous mouse model, confirming several phenotypes relevant to human FTD.To our knowledge, haploinsufficient R493X mice have not previously been studied. Here we assessed whether haploinsufficient GRN 493X mice would demonstrate relevant phenotypes for FTD pathophysiologic studies and drug screening. Method We characterized behavioural and neuropathological phenotypes of aged GRN R493X+/‐, GRN R493X‐/‐ and age‐matched C57BL/6J wildtype mice. The open‐field test was used to assess anxiety phenotype. Brain lysosomal dysfunction was assessed by western blot, and neuroinflammation, including astrogliosis and microgliosis, as well as hippocampal and thalamic synaptic dysfunction were analyzed by immunohistochemistry. Result As expected, our preliminary data show a higher progranulin level in GRN R493X+/‐ mice in comparison with the homozygous GRN R493X mice. Behavioural data, as well as analysis of neuroinflammation, lysosomal dysfunction and brain excitatory and inhibitory synaptic function, are being analyzed and will be presented. Conclusion Heterozygous GRN R493X mice more closely resemble the human genetic condition. Our characterization and comparison of neuropathologic phenotypes in aged GRN R493X+/‐ and GRN R493X‐/‐ mice provide insights into the molecular mechanisms underlying the effects of GRN haploinsufficiency and the suitability of this model for drug screening studies in FTD‐GRN.
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.001 | 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 | 0.002 |
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".