Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.00 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in microglia (80 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: tas0612 | 0.80 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 8 pathways; mostly growth signalling | 0.60 |
Knock down and overexpress RPS6KA1 in microglia; measure phospho-ERK and phospho-AKT response to GDNF and uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release).
- Cell type
- microglia
- Direction
- Both arms: public data does not say which way helps; existing compounds already reach the inhibition arm.
- Molecular readout
- phospho-ERK and phospho-AKT response to GDNF
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves phospho-ERK by 20% or more against non-targeting and empty-vector controls, across three independent differentiations, the hypothesis is wrong.
- Lab request
- CRISPRi knockdown and lentiviral overexpression of RPS6KA1 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: phospho-ERK and phospho-AKT response to GDNF; uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release). Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- RPS6KA1 in microglia, braak-0.23 (p 0.549) → -0.22 (p 0.569)receipt 13522
- RPS6KA1 in dopamine neurons, braak-0.54 (p 0.135) → +0.02 (p 0.964)receipt 13523
Swarm cases
receipt 13523: RPS6KA1 in dopamine neurons, braak
- power
- full sample -0.35 (p 0.153, n 18), 95% CI -0.70 to +0.14. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.33 (p 0.188, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.50 (p 0.035, n 18). not the mix.
- skeptic
- leave-one-out range -0.48 to -0.27, sign flips 0; without severely affected donors -0.35 (p 0.153, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for RPS6KA1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 13522: RPS6KA1 in microglia, braak
- power
- full sample -0.22 (p 0.374, n 18), 95% CI -0.62 to +0.27. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.23 (p 0.360, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.21 (p 0.393, n 18). could be the mix.
- skeptic
- leave-one-out range -0.33 to -0.11, sign flips 0; without severely affected donors -0.22 (p 0.374, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for RPS6KA1 in microglia.
case closed: nothing better to follow up.
Receipts
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