Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.88 (overall 0.60) | 0.88 |
| cell type Human Protein Atlas | expressed broadly, no clear home in brain cells | 0.40 |
| 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 | 83 Parkinson's papers of 129 | 0.42 |
| pathways Reactome | in no curated pathway | 0.00 |
Knock down and overexpress TMEM175 in a dopamine neuron, astrocyte and microglia tri-culture; measure a transcriptome-wide state shift (bulk RNA-seq) and dopamine neuron survival after α-synuclein fibril challenge.
- Cell type
- a dopamine neuron, astrocyte and microglia tri-culture
- Direction
- Both arms: public data does not say which way helps.
- Molecular readout
- a transcriptome-wide state shift (bulk RNA-seq)
- Functional readout
- dopamine neuron survival after α-synuclein fibril challenge
- Rule-out
- If neither arm moves a transcriptome-wide state shift (bulk RNA-seq) 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 TMEM175 in a tri-culture of iPSC dopamine neurons, astrocytes and microglia; n = 3 differentiations; readouts: a transcriptome-wide state shift (bulk RNA-seq); dopamine neuron survival after α-synuclein fibril challenge. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Earlier readings: 2026-10-26 0.58; 2026-10-25 0.58; 2026-10-24 0.58; 2026-10-23 0.58.
Sealed predictions
- TMEM175 in dopamine neurons, braak+0.52 (p 3.8e-4) → +0.47 (p 0.002)held
- TMEM175 in dopamine neurons, braak-0.48 (p 0.187) → -0.09 (p 0.821)receipt 0564
- TMEM175 in dopamine neurons, resilience+0.06 (p 0.823) → +0.38 (p 0.190)receipt 0093
In the sealed studies
- The lysosomal axis in dopamine neurons: did not hold
Swarm cases
receipt 0564: TMEM175 in dopamine neurons, braak
- power
- full sample -0.23 (p 0.360, n 18), 95% CI -0.63 to +0.27. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.27 (p 0.273, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.37 (p 0.135, n 18). could be the mix.
- skeptic
- leave-one-out range -0.42 to -0.16, sign flips 0; without severely affected donors -0.23 (p 0.360, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TMEM175 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0093: TMEM175 in dopamine neurons, resilience
- power
- full sample +0.19 (p 0.323, n 55), 95% CI -0.07 to +0.44. the interval is wide: not enough donors to tell.
- confounder
- adjusted for age, sex and PMI: +0.12 (p 0.556, n 55). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.12 (p 0.542); controlling for it: +0.22 (p 0.256, n 55). could be the mix.
- skeptic
- leave-one-out range +0.12 to +0.31, sign flips 0; without severely affected donors +0.24 (p 0.241, n 46). fragile.
- cell type
- no other cell group does better.
- axis
- braak beats resilience for TMEM175 in dopamine neurons: +0.49 (p 2.1e-6, n 84). proposing braak.
case closed: every proposal failed a challenge.
Receipts
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