Braak stage 1, 100% of pigmented neurons left
parkinsonconnecting

Gene record

PKP2

plakophilin 2

translation score 0.59, read 2026-10-17; 1 sealed predictions, 0 held; 1 receipts.

Six readers

readerfoundscore
genetics
Open Targets		genetic association 0.54 (overall 0.33)0.54
cell type
Human Protein Atlas		expressed broadly, no clear home in brain cells0.40
chemistry
Open Targets		reachable by antibody0.45
trials
ClinicalTrials.gov		no Parkinson's trials on record: an open field1.00
literature
PubMed		1 Parkinson's papers of 5120.91
pathways
Reactome		2 pathways; mostly other0.30
proposal for PKP2, translation score 0.59

Knock down and overexpress PKP2 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 PKP2 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. PKP2 in dopamine neurons, braak+0.04 (p 0.911) → +0.74 (p 0.023)receipt 1071

Swarm cases

receipt 1071: PKP2 in dopamine neurons, braak

power
full sample +0.42 (p 0.082, n 18), 95% CI -0.06 to +0.74. the interval is wide: not enough donors to tell.
confounder
adjusted for sex: +0.43 (p 0.074, n 18). does not hold up.
composition
dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.48 (p 0.043, n 18). not the mix.
skeptic
leave-one-out range +0.35 to +0.50, sign flips 0; without severely affected donors +0.42 (p 0.082, n 18). robust.
cell type
no other cell group does better.
axis
no measure beats "tracks Braak Lewy-body stage" for PKP2 in dopamine neurons.

case closed: nothing better to follow up.

Receipts

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