Distinct Molecular Signatures in α-Synucleinopathies Revealed by Single-Nucleus RNA Sequencing

Overview

This study used single-nucleus RNA sequencing of nearly 300,000 nuclei from the prefrontal cortex to characterize cell type-specific gene expression changes in idiopathic Parkinson’s disease (iPD), LRRK2 mutation-associated PD (LRRK2-PD), and multiple system atrophy (MSA). It identified overlapping transcriptional signatures between iPD and LRRK2-PD that differ from MSA, highlighted a specific deep cortical neuronal subtype with altered expression, and found consistent downregulation of PDE10A across all diseases.

Background

α-Synucleinopathies, including Parkinson’s disease and multiple system atrophy, are neurodegenerative disorders marked by intracellular α-synuclein aggregates. These aggregates differ in cellular localization between diseases, with neuronal Lewy bodies in PD and oligodendroglial inclusions in MSA. Molecular mechanisms underlying neuronal dysfunction remain poorly understood, and prior bulk transcriptomic studies have been confounded by cell composition changes. Single-nucleus RNA sequencing offers cell type-specific resolution to better elucidate disease-related transcriptional alterations.

Data Highlights

Key Findings

• Idiopathic PD and LRRK2-PD share largely overlapping cell type-specific transcriptional signatures distinct from MSA.
• There is an overall decrease in transcriptional output in neurons in iPD and LRRK2-PD.
• A specific deep cortical neuronal subtype expressing adrenoceptor alpha 2A shows concentrated differential gene expression in iPD and LRRK2-PD.
• PDE10A is consistently downregulated across most cortical neurons in all three α-synucleinopathies studied.
• Cell type-specific gene expression signatures correlate with the presence and severity of α-synuclein pathology, including neuronal upregulation of SNCA encoding α-synuclein.

Clinical Implications

These findings highlight the importance of cell type-specific molecular alterations in α-synucleinopathies, suggesting that therapeutic strategies may need to target specific neuronal subtypes and pathways such as PDE10A signaling. The distinct transcriptional profiles between PD forms and MSA underscore the need for tailored approaches in diagnosis and treatment. Additionally, markers associated with α-synuclein pathology could inform disease staging and progression monitoring.

Conclusion

Single-nucleus RNA sequencing reveals distinct and overlapping molecular signatures across α-synucleinopathies, providing novel insights into disease-specific and pathology-associated transcriptional changes at the cellular level. These results advance understanding of the molecular underpinnings of these disorders and may guide future therapeutic development.

References

1. Original Article -- Single-nucleus RNA sequencing uncovers distinct molecular signatures associated with α-synucleinopathies and their related pathologies