Elevated brain α-synuclein, phosphorylated-tau, and oxidative stress in mice that survived influenza A pneumonitis
Bibliographic record
Abstract
ABSTRACT Background Influenza virus exposure elevates the incidence of parkinsonism. We and others previously discovered that allelic variants at the Parkinson’s-linked LRRK2 locus modulate host responses to virulent microbes. Objective We asked whether Lrrk2 mutations modify disease outcomes in adult animals following a nasally acquired lung infection. Methods We inoculated C57BL/6J mice of mutant knock-in Lrrk2 genotypes with influenza A virus, H1N1-serotype (1 x LD 50 = 2,000 plaque-forming units). Results During H1N1-induced pneumonitis neither homozygous nor heterozygous mutations of kinase activity-increasing Lrrk2 G2019S or kinase-dead Lrrk2 D1994S altered the course of sickness in mice when compared to wild-type littermates, as determined by survival rates, viral titres and weight changes in both sexes. However, six weeks after inoculation brains of H1N1-exposed, homozygous Lrrk2 p.G2019S animals showed higher pSer 129 α-synuclein and pSer 199 tau levels than mock-treated, mutant mice ( P<0.01 ). The ratios of phosphorylated tau-to-total tau and phosphorylated α-synuclein-to-total α-synuclein also rose in H1N1-exposed Lrrk2 p.G2019S mice ( P<0.05 ). Further, we found that nitrotyrosination of the brain proteome was significantly increased in Lrrk2 G2019S survivors vs. mock-exposed littermates ( P<0.05 ). Brain H 2 O 2 concentrations were elevated in male, H1N1-inoculated wild-type animals (with a trend seen in females and Lrrk2 G2019S mice), an effect that was abrogated in kinase-dead Lrrk2 D1994S mice. Conclusion Homozygous Lrrk2 G2019S -mutant mice that survived infection by a life-threatening, pneumotropic RNA virus show changes in brain levels of oxidative stress, pSer 199 tau and pSer 129 α-synuclein. These results could be of relevance to the initiation of neurodegeneration-linked changes in humans and may help explain differences in the penetrance rate and expressivity of LRRK2 mutants.
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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 | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".