Braak stage 1, 100% of pigmented neurons left
parkinsonconnecting

Gene record

SIPA1L2

signal induced proliferation associated 1 like 2

translation score 0.58, read 2026-10-16; 2 sealed predictions, 0 held; 2 receipts.

Six readers

readerfoundscore
genetics
Open Targets		genetic association 0.76 (overall 0.47)0.76
cell type
Human Protein Atlas		cell type enhanced, including microglia; strongest in neutrophils0.75
chemistry
Open Targets		hard to drug0.00
trials
ClinicalTrials.gov		no Parkinson's trials on record: an open field1.00
literature
PubMed		10 Parkinson's papers of 370.69
pathways
Reactome		in no curated pathway0.00
proposal for SIPA1L2, translation score 0.58

Knock down and overexpress SIPA1L2 in microglia; measure a transcriptome-wide state shift (bulk RNA-seq) and uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release).

Cell type
microglia
Direction
Both arms: public data does not say which way helps.
Molecular readout
a transcriptome-wide state shift (bulk RNA-seq)
Functional readout
uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
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 SIPA1L2 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: a transcriptome-wide state shift (bulk RNA-seq); uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release). Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.

Sealed predictions

  1. SIPA1L2 in dopamine neurons, braak+0.30 (p 0.428) → -0.04 (p 0.909)receipt 0302
  2. SIPA1L2 in microglia, braak+0.00 (p 1.000) → -0.20 (p 0.597)receipt 0301

Swarm cases

receipt 0302: SIPA1L2 in dopamine neurons, braak

power
full sample +0.01 (p 0.969, n 18), 95% CI -0.46 to +0.47. the interval is wide: not enough donors to tell.
confounder
adjusted for sex: +0.02 (p 0.928, n 18). does not hold up.
composition
dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.06 (p 0.827, n 18). could be the mix.
skeptic
leave-one-out range -0.10 to +0.12, sign flips 7; without severely affected donors +0.01 (p 0.969, n 18). fragile.
cell type
no other cell group does better.
axis
no measure beats "tracks Braak Lewy-body stage" for SIPA1L2 in dopamine neurons.

case closed: nothing better to follow up.

receipt 0301: SIPA1L2 in microglia, braak

power
full sample -0.18 (p 0.482, n 18), 95% CI -0.59 to +0.32. the interval is wide: not enough donors to tell.
confounder
adjusted for sex: -0.20 (p 0.418, n 18). does not hold up.
composition
microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.07 (p 0.781, n 18). could be the mix.
skeptic
leave-one-out range -0.31 to -0.04, sign flips 0; without severely affected donors -0.18 (p 0.482, n 18). fragile.
cell type
no other cell group does better.
axis
no measure beats "tracks Braak Lewy-body stage" for SIPA1L2 in microglia.

case closed: nothing better to follow up.

Receipts

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