Braak stage 1, 100% of pigmented neurons left
parkinsonconnecting

Gene record

PIK3R3

phosphoinositide-3-kinase regulatory subunit 3

translation score 0.56, read 2026-10-25; 1 sealed predictions, 0 held; 1 receipts.

Six readers

readerfoundscore
genetics
Open Targets		no genetic evidence; overall 0.01 from other evidence0.00
cell type
Human Protein Atlas		expressed broadly, no clear home in brain cells0.40
chemistry
Open Targets		compounds already reach it: apitolisib, gedatolisib, taselisib +210.90
trials
ClinicalTrials.gov		no Parkinson's trials on record: an open field1.00
literature
PubMed		2 Parkinson's papers of 2390.85
pathways
Reactome		18 pathways; mostly immune signalling0.90
proposal for PIK3R3, translation score 0.56

Knock down and overexpress PIK3R3 in a dopamine neuron, astrocyte and microglia tri-culture; measure IL-1β and TNF release and surface HLA-DR 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; existing compounds already reach the inhibition arm.
Molecular readout
IL-1β and TNF release and surface HLA-DR
Functional readout
dopamine neuron survival after α-synuclein fibril challenge
Rule-out
If neither arm moves IL-1β 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 PIK3R3 in a tri-culture of iPSC dopamine neurons, astrocytes and microglia; n = 3 differentiations; readouts: IL-1β and TNF release and surface HLA-DR; 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. PIK3R3 in dopamine neurons, braak+0.26 (p 0.504) → +0.17 (p 0.663)receipt 9154

Swarm cases

receipt 9154: PIK3R3 in dopamine neurons, braak

power
full sample +0.21 (p 0.403, n 18), 95% CI -0.28 to +0.62. the interval is wide: not enough donors to tell.
confounder
adjusted for sex: +0.14 (p 0.567, n 18). does not hold up.
composition
dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.26 (p 0.298, n 18). could be the mix.
skeptic
leave-one-out range +0.11 to +0.31, sign flips 0; without severely affected donors +0.21 (p 0.403, n 18). fragile.
cell type
no other cell group does better.
axis
no measure beats "tracks Braak Lewy-body stage" for PIK3R3 in dopamine neurons.

case closed: nothing better to follow up.

Receipts

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