Pharmacological inhibition and knockdown of O‐GlcNAcase reduces cellular internalization of α‐synuclein preformed fibrils
Bibliographic record
Abstract
The pathological hallmark of Parkinson's disease (PD) is Lewy bodies that form within the brain from aggregated forms of α-synuclein (α-syn). These toxic α-syn aggregates are transferred from cell to cell by release of fibrils from dying neurons into the extracellular environment, followed by their subsequent uptake by neighboring cells. This process leads to spreading of the pathology throughout the brain in a prion-like manner. Identifying new pathways that hinder the internalization of such α-syn fibrils is of high interest for their downstream potential exploitation as a way to create disease-modifying therapeutics for PD. Here, we show that Thiamet-G, a highly selective pharmacological agent that inhibits the glycoside hydrolase O-GlcNAcase (OGA), blunts the cellular uptake of α-syn fibrils. This effect correlates with increased nucleocytoplasmic levels of O-linked N-acetylglucosamine (O-GlcNAc)-modified proteins, and genetic knockdown of OGA expression closely phenocopies both these effects. These reductions in the uptake of α-syn fibrils caused by inhibition of OGA are both concentration- and time-dependent and are observed in multiple cell lines including mouse primary cortical neurons. Moreover, treatment of cells with the OGT inhibitor, 5SGlcNHex, increases the level of uptake of α-syn PFFs, further supporting O-GlcNAcylation of proteins driving these effects. Notably, this effect is mediated through an unknown mechanism that does not involve well-characterized endocytotic pathways. These data suggest one mechanism by which OGA inhibitors might exert their protective effects in prion-like neuropathologies and support exploration of OGA inhibitors as a potential disease-modifying approach to treat PD.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".