A role for LRRK2 and Neuroinflammatory Processes in Multi-Hit Toxicant Models of Parkinson’s Disease
Bibliographic record
Abstract
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra (SNc) leading to a range of motor behavioral deficits.In addition to the cardinal motor features of the disease, non-motor behaviors are also evident in many cases.Although it has been suggested that genetic mutations represent a cause or risk factor for the disease, there is evidence to suggest that PD arises as a result of the interaction between multiple factors.In the current dissertation, one overarching theme we were interested in was how the behavioral and neurochemical effects of the PD relevant herbicide paraquat (a chemical stressor) might be impacted when combined with different stressors including chronic psychological stress, immune stress, or age induced alterations.Furthermore, we were also highly interested in providing further understanding regarding the role of neuroinflammatory processes (as occurs in PD) in the paraquat induced death of SNc dopamine neurons.In these instances, we focused on the inflammatory regulatory gene (and number one gene implicated in PD), leucine rich repeat kinase 2 (LRRK2).Accordingly, in our study combining paraquat exposure with a chronic unpredictable stress regimen, we found that chronic psychological stressor exposure did not influence the degeneration of midbrain dopamine neurons or accompanying microglia activation induced by the toxin; however, it did influence motor coordination.Conversely, exposure of the pesticide in combination with the inflammatory agent lipopolysaccharide (LPS) augmented SNc cell loss.In these studies using LPS, we found that knocking out LRRK2 protected against the loss of midbrain dopamine Rudyk iii neurons and behavioral deficits, induced by LPS priming followed by paraquat exposure.In fact, knocking out LRRK2 altered the pro-inflammatory microglia phenotype that is typically induced by LPS exposure.Likewise, LRRK2 deficiency protected against the paraquat induced peripheral and central toxic effects in mice older than what we typically use in our models.Taken together, the present dissertation supports the hypothesis that the interaction between different stressors can impact behavioral and biological outcomes relevant for PD, and LRRK2 is important for the toxic effects of paraquat, and LPS priming with later paraquat exposure.The data presented herein may also provide important implications for the development of treatment strategies that target inflammatory processes in PD, to halt or slow the progression of the disease.
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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 | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".