parkinson-tcell-foothold-r3

Ma, J., Al-Dalahmah, O., Goldman, J.E., Sulzer, D., Sims, P.A. et al. (Nat Commun s41467-025-62478-3, 2025; PMC12322057) reported spatially resolved adaptive immunity in Parkinson's disease substantia nigra: combined snRNA-seq + 10x Visium + scTCR-seq across 44 donors (13 PD + 15 ctrl SN; 10 PD + 8 ctrl cingulate; 265,284 nuclei + 10 donors with Visium) identified clonally expanded CD8+ T cells whose TCRs share homology with α-synuclein peptides and which spatially co-localise with CD44+ reactive astrocytes in PD SN.

The Ma 2025 result depends on rare TCR-seq data, which the Kamath 2022 (GSE178265), Wang 2024 (GSE184950), Adams 2024 (GSE193688) and Fullard 2024 multi-region atlases do not have. The question is whether the transcriptomic footprint of the Ma-2025 T-cell signature (the genes co-expressed in the clonally expanded CD8+ population) can be detected in those four independent atlases, in a deconvolution-inferred T-cell or lymphocyte cluster, without TCR ground truth.

Hypotheses (pre-registered):

H1 (primary — transcriptomic footprint replicates in independent PD snRNA-seq atlases): The Ma 2025-defined T-cell signature (extracted from Supplementary Data of PMC12322057 — the top-50 differentially expressed genes in the clonally expanded CD8+ population vs. all other immune nuclei in PD SN) is scored per cell in T-cell / lymphocyte clusters of:

• Kamath 2022 (GSE178265) SNpc + caudate

• Wang 2024 (GSE184950) SNpc

• Adams 2024 (GSE193688) SN

• Fullard 2024 SNpc + M1 (CELLxGENE d5d0df8f-...) and tested for PD-vs-control per-donor pseudobulk differential at FDR<0.1. At least 3 of 4 atlases show log2FC > 0 in the T-cell-module score in the PD direction.

H2 (secondary — region specificity within multi-region atlas): Within the Fullard atlas (the only multi-region atlas in the panel), the T-cell-module signal is significantly higher in SNpc + cingulate-like cortical regions than in DMNX (Braak 1, vagal-driven, no expected adaptive immune component) or V1 (Braak 6, late-stage, no expected ongoing immune infiltration). Pre-registered ranking: SNpc > M1 > V1 ≈ DMNX. Spearman ρ on rank vs. signature score > 0.5, permutation p < 0.05.

H3 (secondary — T-cell-module × DA-loss covariation): At the donor level, in Kamath / Wang / Adams / Fullard atlases, the T-cell-module pseudobulk score is positively correlated with the AGTR1+ DA-loss score (computed identically to parkinson-da-vulnerability proposal): donors with more T-cell signal also have more vulnerable- DA loss. Spearman ρ > 0.3, permutation p < 0.05 in ≥ 2 of 4 atlases.

H4 (secondary — astrocyte co-localisation in spatial slabs): Where Visium-spatial data is available (Martirosyan A5, Ma 2025 itself), spatial spots scoring high for the T-cell module are also enriched for CD44+ / GFAP-high reactive astrocyte markers (Ma 2025's reported co-localisation), with Spearman ρ > 0.3 on per-spot z-scored module scores.

H5 (secondary — non-α-syn-homology bound — negative control): We pre-register a non-PD-relevant T-cell sub-signature (a generic exhaustion module: PDCD1, HAVCR2, LAG3, TOX, TIGIT) as a negative control. The exhaustion module should NOT show preferential PD enrichment (this signal is canonical to tumor immunology and PD T cells are not exhausted in the same way). A positive enrichment of the exhaustion module would suggest the H1 signal is a non-specific "T cell present" signal rather than a PD-specific clonally-expanded program.

A null result on H1 is informative: it would mean that without TCR-seq ground truth, the clonal-expansion signal in Ma 2025 is not detectable from gene expression alone — calling into question any retrospective inference of adaptive immunity from existing PD snRNA-seq atlases.

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