Braak stage 1, 100% of pigmented neurons left
parkinsonconnecting

Gene record

HACE1

HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1

translation score 0.60, read 2026-10-18; 1 sealed predictions, 0 held; 1 receipts.

Six readers

readerfoundscore
genetics
Open Targets		genetic association 0.28 (overall 0.18)0.28
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		2 Parkinson's papers of 1460.85
pathways
Reactome		2 pathways; mostly immune signalling0.90
proposal for HACE1, translation score 0.60

Knock down and overexpress HACE1 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.
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 HACE1 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. HACE1 in dopamine neurons, braak+0.06 (p 0.877) → +0.47 (p 0.199)receipt 2108

Swarm cases

receipt 2108: HACE1 in dopamine neurons, braak

power
full sample +0.35 (p 0.156, n 18), 95% CI -0.14 to +0.70. 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: +0.39 (p 0.111, n 18). could be the mix.
skeptic
leave-one-out range +0.26 to +0.47, sign flips 0; without severely affected donors +0.35 (p 0.156, n 18). fragile.
cell type
no other cell group does better.
axis
no measure beats "tracks Braak Lewy-body stage" for HACE1 in dopamine neurons.

case closed: nothing better to follow up.

Receipts

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