Front Aging Neurosci. 2026 May 19;18:1806505. doi: 10.3389/fnagi.2026.1806505. eCollection 2026.
ABSTRACT
BACKGROUND: Parkinson’s disease (PD) involves progressive dopaminergic neuron loss in the substantia nigra (SN). Aldehyde dehydrogenase 1A1 (ALDH1A1), the rate-limiting enzyme in retinoic acid biosynthesis, is enriched in vulnerable dopaminergic neuron subpopulations and is consistently downregulated in PD. However, the relationship between ALDH1A1 expression and broader dopaminergic pathway gene co-expression has not been systematically characterized across multiple independent datasets.
METHODS: Gene expression correlations were analyzed across seven independent human SN microarray datasets (n = 156; 70 controls, 86 PD) from the Gene Expression Omnibus. Simple arithmetic means across datasets are reported as the primary summary statistic; random-effects meta-analysis with DerSimonian-Laird estimation was applied to Fisher’s z-transformed correlation coefficients to generate pooled estimates with heterogeneity statistics. Marker gene-based enrichment scoring using published cell type markers from single-nucleus RNA-seq profiling of human substantia nigra-with all target genes excluded from signatures-was performed across six analyzable datasets. Selectivity of ALDH1A1 correlation attenuation was assessed using permutation testing (n = 5,000) as the primary statistical test, with parametric tests reported as supplementary.
RESULTS: In controls, ALDH1A1 showed strong co-expression with dopaminergic genes (mean r = 0.92-0.93 for TH, DDC, and SLC18A2). In PD, these correlations were attenuated (mean Δr = -0.336 for ALDH1A1-dopamine pairs). Dopamine-dopamine correlations showed less attenuation (mean Δr = -0.143). Marker gene-based enrichment scoring confirmed significant depletion of ALDH1A1-positive vulnerable dopaminergic neurons in 4 of 6 datasets. After adjusting for estimated cell type enrichment, the selectivity of ALDH1A1 attenuation was preserved (adjusted selectivity: -0.210, increased from raw selectivity of -0.190; raw permutation p = 0.0052).
CONCLUSION: ALDH1A1 co-expression with dopaminergic pathway genes is attenuated in PD substantia nigra across all seven datasets examined. This attenuation is selective for ALDH1A1-containing pairs, and this selectivity persists after adjusting for cell type enrichment changes. While correlational, these findings are consistent with a role for retinoic acid pathway disruption in PD pathophysiology and warrant mechanistic investigation.
PMID:42239820 | PMC:PMC13226206 | DOI:10.3389/fnagi.2026.1806505
