Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.21 (overall 0.16) | 0.21 |
| cell type Human Protein Atlas | cell type enhanced, including astrocytes; strongest in retinal bipolar cells | 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 | 3 Parkinson's papers of 652 | 0.82 |
| pathways Reactome | 10 pathways; mostly protein handling | 0.90 |
Knock down and overexpress RORA in astrocytes; measure proteasome activity and the load of ubiquitinated protein 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
- proteasome activity and the load of ubiquitinated protein
- Functional readout
- α-synuclein uptake and degradation, and dopamine neuron survival in co-culture
- Rule-out
- If neither arm moves proteasome activity 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 RORA in iPSC-derived midbrain astrocytes; n = 3 differentiations; readouts: proteasome activity and the load of ubiquitinated protein; 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
- RORA in dopamine neurons, braak+0.09 (p 0.822) → +0.07 (p 0.849)receipt 2174
- RORA in astrocytes, braak+0.47 (p 0.199) → -0.36 (p 0.344)receipt 2173
Swarm cases
receipt 2174: RORA in dopamine neurons, braak
- power
- full sample +0.09 (p 0.709, n 18), 95% CI -0.39 to +0.54. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.06 (p 0.807, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.04 (p 0.874, n 18). could be the mix.
- skeptic
- leave-one-out range -0.01 to +0.23, sign flips 3; without severely affected donors +0.09 (p 0.709, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for RORA in dopamine neurons.
case closed: nothing better to follow up.
receipt 2173: RORA in astrocytes, braak
- power
- full sample +0.22 (p 0.389, n 18), 95% CI -0.28 to +0.62. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.21 (p 0.393, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: +0.29 (p 0.246, n 18). could be the mix.
- skeptic
- leave-one-out range +0.11 to +0.36, sign flips 0; without severely affected donors +0.22 (p 0.389, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for RORA in astrocytes.
case closed: nothing better to follow up.
Receipts
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