Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.01 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including astrocytes; strongest in lactotrophs | 0.75 |
| 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 | 3 Parkinson's papers of 87 | 0.82 |
| pathways Reactome | 7 pathways; mostly growth signalling | 0.60 |
Knock down and overexpress RPS6KA2 in astrocytes; measure phospho-ERK and phospho-AKT response to GDNF and α-synuclein uptake and degradation, and dopamine neuron survival in co-culture.
- Cell type
- astrocytes
- 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
- α-synuclein uptake and degradation, and dopamine neuron survival in co-culture
- 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 RPS6KA2 in iPSC-derived midbrain astrocytes; n = 3 differentiations; readouts: phospho-ERK and phospho-AKT response to GDNF; α-synuclein uptake and degradation, and dopamine neuron survival in co-culture. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- RPS6KA2 in dopamine neurons, braak-0.50 (p 0.174) → -0.59 (p 0.096)receipt 11712
- RPS6KA2 in astrocytes, braak+0.05 (p 0.894) → +0.10 (p 0.802)receipt 11711
Swarm cases
receipt 11712: RPS6KA2 in dopamine neurons, braak
- power
- full sample -0.31 (p 0.207, n 18), 95% CI -0.68 to +0.18. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.31 (p 0.207, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.42 (p 0.082, n 18). could be the mix.
- skeptic
- leave-one-out range -0.39 to -0.23, sign flips 0; without severely affected donors -0.31 (p 0.207, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for RPS6KA2 in dopamine neurons.
case closed: nothing better to follow up.
receipt 11711: RPS6KA2 in astrocytes, braak
- power
- full sample +0.13 (p 0.621, n 18), 95% CI -0.36 to +0.56. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.03 (p 0.901, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: +0.06 (p 0.820, n 18). could be the mix.
- skeptic
- leave-one-out range -0.01 to +0.27, sign flips 1; without severely affected donors +0.13 (p 0.621, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for RPS6KA2 in astrocytes.
case closed: nothing better to follow up.
Receipts
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