Braak stage 1, 100% of pigmented neurons left
parkinsonconnecting

Gene record

FLG

filaggrin

translation score 0.58, read 2026-10-17; 1 sealed predictions, 0 held; 1 receipts.

Six readers

readerfoundscore
genetics
Open Targets		genetic association 0.73 (overall 0.44)0.73
cell type
Human Protein Atlas		cell type enriched outside the brain (esophageal apical cells)0.10
chemistry
Open Targets		reachable by antibody0.45
trials
ClinicalTrials.gov		1 Parkinson's trial, 0 stopped1.00
literature
PubMed		5 Parkinson's papers of 1,7360.76
pathways
Reactome		2 pathways; mostly other0.30
proposal for FLG, translation score 0.58

Knock down and overexpress FLG 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 FLG 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.

Sealed predictions

  1. FLG in dopamine neurons, braak-0.41 (p 0.277) → -0.24 (p 0.533)receipt 0442

Swarm cases

receipt 0442: FLG in dopamine neurons, braak

power
full sample -0.26 (p 0.294, n 18), 95% CI -0.65 to +0.23. the interval is wide: not enough donors to tell.
confounder
adjusted for sex: -0.26 (p 0.294, n 18). does not hold up.
composition
dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.44 (p 0.067, n 18). could be the mix.
skeptic
leave-one-out range -0.39 to -0.16, sign flips 0; without severely affected donors -0.26 (p 0.294, n 18). fragile.
cell type
no other cell group does better.
axis
no measure beats "tracks Braak Lewy-body stage" for FLG in dopamine neurons.

case closed: nothing better to follow up.

Receipts

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