NeuralCipher Research overview
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Abstract Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra. However, the metabolic mechanisms linking neuronal vulnerability to ferroptosis remain poorly understood. To address this question, we integrated single-nucleus and bulk RNA sequencing datasets from human substantia nigra to characterize cell-type-specific transcriptional alterations in PD. Integrative transcriptomic analyses including Weighted gene co-expression network analysis, pathway enrichment analysis, and correlation analysis, were further validated using MPTP-induced mouse models and MPP⁺-treated SH-SY5Y cells combined with gene silencing and ferroptosis-related assays. In addition, structure-based virtual screening of 12,316 DrugBank compounds was conducted to identify potential modulators of key metabolic targets. We found that dopaminergic neurons exhibited preferential activation of ferroptosis signatures accompanied by marked dysregulation of amino acid metabolic pathways. Among metabolism-related genes, argininosuccinate synthase 1 (ASS1) emerged as a key candidate with favorable diagnostic performance and significant positive correlations with ferroptosis-suppressive genes, including GPX4 and GSS. In MPTP-induced mice, ASS1 expression was significantly reduced in the substantia nigra and dopaminergic neurons. Consistently, ASS1 silencing in MPP⁺-treated SH-SY5Y cells further decreased cell viability and reduced TH and GPX4 expression, while markedly increasing lipid peroxidation, indicating enhanced ferroptosis susceptibility. Virtual screening further identified several therapeutically relevant compounds with favorable predicted binding to an ASS1 docking pocket. Collectively, these findings identify ASS1-associated amino acid metabolic impairment as a prominent feature of dopaminergic ferroptosis in PD and highlight ASS1 as a potential therapeutic target for neuroprotective intervention.
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