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 adipocytes | 0.75 |
| chemistry Open Targets | a small-molecule pocket | 0.60 |
| 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 | 3 pathways; mostly growth signalling | 0.60 |
Knock down and overexpress MRAS 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.
- 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 MRAS 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
- MRAS in dopamine neurons, braak+0.23 (p 0.549) → -0.48 (p 0.195)receipt 11345
- MRAS in astrocytes, braak-0.91 (p 5.7e-4) → -0.47 (p 0.197)receipt 11344
Swarm cases
receipt 11345: MRAS in dopamine neurons, braak
- power
- full sample -0.08 (p 0.761, n 18), 95% CI -0.53 to +0.40. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.07 (p 0.787, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.17 (p 0.498, n 18). could be the mix.
- skeptic
- leave-one-out range -0.25 to +0.02, sign flips 5; without severely affected donors -0.08 (p 0.761, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for MRAS in dopamine neurons.
case closed: nothing better to follow up.
receipt 11344: MRAS in astrocytes, braak
- power
- full sample -0.57 (p 0.014, n 18), 95% CI -0.82 to -0.14. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: -0.57 (p 0.014, n 18). holds up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: -0.52 (p 0.027, n 18). not the mix.
- skeptic
- leave-one-out range -0.69 to -0.50, sign flips 0; without severely affected donors -0.57 (p 0.014, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for MRAS in astrocytes.
case closed: nothing better to follow up.
Receipts
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