parkinson-lincs-reversal-r4

Which approved or late-phase compounds in the LINCS L1000 Phase II touchstone library produce gene-expression signatures that maximally reverse the PD-vs-control transcriptomic signature of SNpc dopaminergic neurons (Fullard 2024) — and how many of the top-50 reversing candidates have prior PD-drug-repositioning evidence in Open Targets or in published PD repurposing hit lists?

LINCS L1000-based drug repositioning was pioneered by Iorio 2010 and applied broadly across diseases (CMAP score). PD applications have used bulk or whole-tissue signatures — never a cell-type-resolved, snRNA-seq-derived SNpc-DA-neuron signature from a multi-region atlas. The known concern is that LINCS L1000 cell lines are mostly cancer lines (MCF7, PC3, A375, etc.) and may be biologically irrelevant to neurons. This OmiCairn run tests exactly that.

Hypotheses (pre-registered):

H1 (primary — top-50 reversers overlap with prior PD evidence): ≥ 5 of the top-50 negatively-correlated (most reversing) compounds by LINCS L1000 connectivity score against the SNpc-DA PD-vs-ctrl signature have prior Open Targets PD association (overall_association_score > 0 for MONDO:0005180) OR have appeared in a published PD drug-repositioning hit list (Bayati 2024 Acta Neuro DDC paper; omicSynth Tang 2024; Storm 2025). Hypergeometric q < 0.01 over background of all L1000 small-molecule perturbagens.

H2 (secondary — drug-class enrichment): The top-50 hits are enriched for known PD-relevant therapeutic classes — anti-inflammatory, mTOR modulators, calcium-channel blockers, anti-oxidants, autophagy inducers. Pre-registered: ≥ 2 of these 5 classes over-represented by Fisher's exact q < 0.05.

H3 (secondary — cell-type-specific reversal): Reversal scores in DA neurons differ from reversal scores in microglia from the same Fullard atlas (Pearson r < 0.3 for the two L1000 connectivity ranking lists). The optimal repurposing candidate is cell-type-dependent, not a global brain signal.

H4 (secondary — neuronal-cell-line subset analysis): Restrict L1000 to its neuronal subset (NEU, NPC cell-line signatures only) — n = 2 cell lines, much smaller library. Test whether the neuronal-subset top-50 reversers have higher overlap with prior PD evidence (≥ 8 of 50) than the all-cell-lines top-50 (H1).

H5 (secondary — sign-direction sanity check): Internal positive control: levodopa (DDC substrate) and ropinirole (D2 agonist) should appear in the positive connectivity tail (mimic PD-on-treatment state), NOT in the reversing tail. If they appear in the reversing tail, the signature direction is wrong.

Null payoff. A null overlap (H1: 0/50 with prior PD evidence) means LINCS L1000 cancer-line transcriptomic signatures are too non-neuronal to be informative for PD — an informative quantification of the long-suspected limitation.

The research question comes from the topic's current research brief. All attempts at a topic share it; earlier attempts may have started from an earlier wording.