A Transcriptomic Roadmap of Parkinson's Disease Progression at Single Cell Resolution.

Area of Science:

• Neuroscience
• Genomics
• Cell Biology

Background:

• Parkinson's disease (PD) is a progressive neurodegenerative disorder with poorly understood molecular pathology.
• The cellular architecture and progression of PD across different brain regions remain unclear.

Purpose of the Study:

• To create a comprehensive single-nucleus transcriptomic atlas of PD across multiple brain regions.
• To define cell subtypes and identify cell-type-specific gene expression changes in PD.
• To link genetic risk factors to molecular pathology and uncover therapeutic targets.

Main Methods:

• Single-nucleus RNA sequencing (snRNA-seq) of over 2 million nuclei from 97 PD donors.
• Bioinformatic analysis to define cell subtypes and gene expression patterns.
• Integrative analysis of transcriptomic data with PD genetic risk (GWAS) and Braak staging.

Main Results:

• Defined 62 distinct cell subtypes with widespread, cell-type-specific gene expression changes.
• Identified convergent upregulation of stress-response pathways (UPR, DNA damage repair, autophagy) across multiple cell types.
• Developed a transcriptomic pathology score showing early neuronal and myeloid activation, followed by vascular cell engagement.
• Revealed dynamic microglial transitions and altered myeloid-neuronal communication networks throughout PD progression.
• Linked PD genetic risk loci to specific transcription factor-target gene networks in microglia and neurons.

Conclusions:

• This atlas provides a foundational resource for understanding PD at single-cell resolution.
• It reveals dynamic molecular pathology and cell-type-specific responses during PD progression.
• Identified stage-specific cellular changes and neuroimmune interactions offer potential therapeutic targets for PD.