Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.09 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in astrocytes (55 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: nerispirdine, amifampridine, guanidine hydrochloride +3 | 1.00 |
| trials ClinicalTrials.gov | 6 Parkinson's trials, 1 stopped | 0.87 |
| literature PubMed | 1 Parkinson's papers of 179 | 0.91 |
| pathways Reactome | 1 pathway; mostly dopamine synapse | 1.00 |
Knock down and overexpress KCNA2 in astrocytes; measure evoked dopamine release and dopamine transporter uptake 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
- evoked dopamine release and dopamine transporter uptake
- Functional readout
- α-synuclein uptake and degradation, and dopamine neuron survival in co-culture
- Rule-out
- If neither arm moves evoked dopamine release 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 KCNA2 in iPSC-derived midbrain astrocytes; n = 3 differentiations; readouts: evoked dopamine release and dopamine transporter uptake; 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
- KCNA2 in dopamine neurons, braak-0.36 (p 0.348) → -0.42 (p 0.262)receipt 3106
- KCNA2 in astrocytes, braak+0.31 (p 0.414) → +0.78 (p 0.014)receipt 3105
Swarm cases
receipt 3106: KCNA2 in dopamine neurons, braak
- power
- full sample -0.32 (p 0.191, n 18), 95% CI -0.69 to +0.17. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.31 (p 0.214, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.54 (p 0.020, n 18). not the mix.
- skeptic
- leave-one-out range -0.39 to -0.23, sign flips 0; without severely affected donors -0.32 (p 0.191, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for KCNA2 in dopamine neurons.
case closed: nothing better to follow up.
receipt 3105: KCNA2 in astrocytes, braak
- power
- full sample +0.38 (p 0.116, n 18), 95% CI -0.10 to +0.72. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.45 (p 0.063, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: +0.50 (p 0.036, n 18). not the mix.
- skeptic
- leave-one-out range +0.28 to +0.54, sign flips 0; without severely affected donors +0.38 (p 0.116, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for KCNA2 in astrocytes.
case closed: nothing better to follow up.
Receipts
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