Braak stage 1, 100% of pigmented neurons left
parkinsonconnecting

Gene record

HERC3

HECT and RLD domain containing E3 ubiquitin protein ligase 3

translation score 0.57, read 2026-10-20; 2 sealed predictions, 0 held; 2 receipts.

Six readers

readerfoundscore
genetics
Open Targets		no genetic evidence; overall 0.06 from other evidence0.00
cell type
Human Protein Atlas		cell type enhanced in microglia (184 nCPM)1.00
chemistry
Open Targets		hard to drug0.00
trials
ClinicalTrials.gov		no Parkinson's trials on record: an open field1.00
literature
PubMed		no papers tie it to Parkinson's yet1.00
pathways
Reactome		1 pathway; mostly immune signalling0.90
proposal for HERC3, translation score 0.57

Knock down and overexpress HERC3 in microglia; measure IL-1β and TNF release and surface HLA-DR 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
IL-1β and TNF release and surface HLA-DR
Functional readout
uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
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 HERC3 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: IL-1β and TNF release and surface HLA-DR; 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. HERC3 in microglia, braak-0.10 (p 0.807) → +0.38 (p 0.309)receipt 4623
  2. HERC3 in dopamine neurons, braak-0.26 (p 0.498) → +0.23 (p 0.554)receipt 4624

Swarm cases

receipt 4624: HERC3 in dopamine neurons, braak

power
full sample -0.02 (p 0.935, n 18), 95% CI -0.48 to +0.45. the interval is wide: not enough donors to tell.
confounder
adjusted for sex: +0.09 (p 0.715, n 18). does not hold up.
composition
dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.01 (p 0.976, n 18). could be the mix.
skeptic
leave-one-out range -0.16 to +0.11, sign flips 6; without severely affected donors -0.02 (p 0.935, n 18). fragile.
cell type
no other cell group does better.
axis
no measure beats "tracks Braak Lewy-body stage" for HERC3 in dopamine neurons.

case closed: nothing better to follow up.

receipt 4623: HERC3 in microglia, braak

power
full sample +0.15 (p 0.555, n 18), 95% CI -0.34 to +0.58. the interval is wide: not enough donors to tell.
confounder
adjusted for sex: +0.11 (p 0.652, n 18). does not hold up.
composition
microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.20 (p 0.429, n 18). could be the mix.
skeptic
leave-one-out range +0.04 to +0.25, sign flips 0; without severely affected donors +0.15 (p 0.555, n 18). fragile.
cell type
no other cell group does better.
axis
no measure beats "tracks Braak Lewy-body stage" for HERC3 in microglia.

case closed: nothing better to follow up.

Receipts

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