Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.07 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in microglia (21 nCPM) | 1.00 |
| chemistry Open Targets | reachable by antibody | 0.45 |
| trials ClinicalTrials.gov | 1 Parkinson's trial, 0 stopped | 1.00 |
| literature PubMed | 11 Parkinson's papers of 913 | 0.67 |
| pathways Reactome | 1 pathway; mostly lysosome and autophagy | 1.00 |
Knock down and overexpress CLN3 in microglia; measure glucocerebrosidase (GCase) activity and LC3-II and p62 flux 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.
- Molecular readout
- glucocerebrosidase (GCase) activity and LC3-II and p62 flux
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves glucocerebrosidase (GCase) 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 CLN3 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: glucocerebrosidase (GCase) activity and LC3-II and p62 flux; 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
- CLN3 in dopamine neurons, braak+0.22 (p 0.569) → -0.35 (p 0.360)receipt 3713
- CLN3 in microglia, braak+0.06 (p 0.888) → -0.18 (p 0.646)receipt 3712
Swarm cases
receipt 3713: CLN3 in dopamine neurons, braak
- power
- full sample -0.13 (p 0.621, n 18), 95% CI -0.56 to +0.36. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.10 (p 0.696, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.07 (p 0.787, n 18). could be the mix.
- skeptic
- leave-one-out range -0.29 to -0.05, sign flips 0; 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 CLN3 in dopamine neurons.
case closed: nothing better to follow up.
receipt 3712: CLN3 in microglia, braak
- power
- full sample -0.09 (p 0.709, n 18), 95% CI -0.54 to +0.39. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.09 (p 0.728, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.04 (p 0.888, n 18). could be the mix.
- skeptic
- leave-one-out range -0.20 to +0.02, 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 CLN3 in microglia.
case closed: nothing better to follow up.
Receipts
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