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Parkinson’s disease blood biomarkers correspond to a selectively vulnerable group of dopaminergic neurons

ABSTRACT: Blood mRNA biomarker validation of the Luxembourgish PD cohort by single cell RNAseq in GBA-PD midbrain organoids identifies a PD vulnerable dopaminergic neuron subcluster, with transcriptionally overactive mitochondria that is lost upon PD. Deep phenotyping of patient derived GBA-N409S midbrain organoids confirms the altered mitochondrial activity, increased ROS and TH+ dopaminergic neuronal cell loss in PD. To identify molecular targets underlying the increased dopaminergic vulnerability in GBA-N409S midbrain organoids blood cohort mRNA and miRNA biomarkers were integrated, revealing ALDH1A1, an aldehyde dehydrogenase involved in dopamine metabolism and reactive aldehyde clearance as potential candidate gene. Moreover, cohort metabolite biomarker validation revealed retinoic acid metabolism as potential pathway involved in ALDH1A1 dependent dopaminergic susceptibility. Whereas toxin induced ALDH1A1 reduction alone was not sufficient to induce dopaminergic neuron cell death in healthy organoids retinoic acid treatment rescued GBA-N409S dopaminergic neuron loss in GBA-N409S PD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278769 | GEO | 2025/01/01

REPOSITORIES: GEO

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