parkinson-metabolic-flux-sn-r1

When the human genome-scale metabolic model Recon3D / Human-GEM is contextualised to PD-vs-control substantia-nigra pseudobulk expression (Fullard 2024 atlas, DA-neuron subset) via iMAT, do the predicted flux changes recapitulate the Supandi 2018 cortical-bulk findings (decreased glycolysis, decreased TCA flux midway, increased lactate) specifically inside dopaminergic neurons — a cell type that bulk microarray averages over?

Supandi 2018 used PLOS One bulk microarray on PD cortex and predicted lower glycolytic and TCA flux. Their bulk preparation could not address SNpc DA neurons specifically. The 2024 Yamamori TIMBR paper (J Biotechnol Adv) extended GEM-based PD metabolic-biomarker prediction across 13 SN datasets, but remained bulk. Single-cell snRNA-seq atlases now make a DA-neuron-context constraint-based flux analysis possible. This OmiCairn run is the first to attempt it on Fullard data.

Hypotheses (pre-registered):

H1 (primary — cortex-bulk concordance + DA glycolysis): In Recon3D contextualised by iMAT on Fullard SNpc DA pseudobulk, the PD-vs-control predicted flux change in cytoplasmic glycolysis (reactions PGK / HEX1 / PFK / ENO1 + 4 supporting reactions) is negative, with median signed flux ratio < 0.9 and bootstrap 95% CI excluding 1.0 (10,000 donor bootstraps). Sign concordance with Supandi 2018 cortical-bulk predictions on shared reactions is ≥ 70% (binomial test p < 0.01 against null 0.5).

H2 (secondary — TIMBR biomarker recovery): TIMBR-predicted top-10 PD biomarker metabolites (Yamamori 2024) recover ≥ 4 metabolites whose abundance is also flagged by the Shao 2024 npj-PD plasma+CSF metabolomics meta-analysis (Supplementary Table 1) — a hypergeometric q < 0.05 cross-resource check.

H3 (secondary — iron-metabolism elevation): Iron-metabolism flux (FECH-, FTH1-, TFRC-dependent reactions) is elevated in DA-neuron-context PD-vs-control flux ratio > 1.1 with bootstrap 95% CI excluding 1.0, consistent with the iron-accumulation vulnerability hypothesis (Hong 2025 PD-iron).

H4 (secondary — contextualisation-method concordance): Repeat the analysis with three contextualisation methods — iMAT, TIMBR, E-Flux — and report Spearman ρ across per-reaction PD-vs-ctrl flux changes. ρ ≥ 0.5 between any two methods is the minimum agreement bar. (Per the v2 risk register, this is the dominant failure mode for constraint-based PD flux work.)

H5 (secondary — DA-vs-glia cell-type separation): Repeat the analysis with Fullard microglia pseudobulk instead of DA-neuron pseudobulk. If H1's glycolysis-down finding is reproduced only in DA neurons and not in microglia, the bulk Supandi finding is DA-neuron-driven. If it is reproduced in both, bulk Supandi was averaging an organ-wide signal. Both outcomes are informative.

Null payoff. A null DA-neuron H1 (median flux ratio ≥ 0.9 or bootstrap CI overlapping 1.0) means Supandi's bulk findings were driven by non-DA cell types (likely glia), not the vulnerable neurons themselves. Biologically informative.

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