Braak stage 1, 100% of pigmented neurons left
parkinsonconnecting

Gene record

SPPL2B

signal peptide peptidase like 2B

translation score 0.57, read 2026-10-18; 1 sealed predictions, 0 held; 1 receipts.

Six readers

readerfoundscore
genetics
Open Targets		genetic association 0.39 (overall 0.25)0.39
cell type
Human Protein Atlas		expressed broadly, no clear home in brain cells0.40
chemistry
Open Targets		a small-molecule pocket0.60
trials
ClinicalTrials.gov		no Parkinson's trials on record: an open field1.00
literature
PubMed		1 Parkinson's papers of 360.91
pathways
Reactome		1 pathway; mostly other0.30
proposal for SPPL2B, translation score 0.57

Knock down and overexpress SPPL2B 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 SPPL2B 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. SPPL2B in dopamine neurons, braak-0.07 (p 0.855) → -0.19 (p 0.619)receipt 1730

Swarm cases

receipt 1730: SPPL2B in dopamine neurons, braak

power
full sample -0.13 (p 0.609, n 18), 95% CI -0.56 to +0.36. the interval is wide: not enough donors to tell.
confounder
adjusted for sex: -0.13 (p 0.621, n 18). does not hold up.
composition
dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.32 (p 0.191, n 18). could be the mix.
skeptic
leave-one-out range -0.22 to -0.00, sign flips 0; without severely affected donors -0.13 (p 0.609, n 18). fragile.
cell type
no other cell group does better.
axis
no measure beats "tracks Braak Lewy-body stage" for SPPL2B in dopamine neurons.

case closed: nothing better to follow up.

Receipts

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