Longitudinal Multi-Omics in Alpha-Synuclein Drosophila Model Discriminates Disease- From Age-Associated Pathologies in Parkinson’s Disease

Authors

Justin Moore
Timothy Wu
Justin Dhindsa
Omar El Fadel
Anh Le
Alma Perez
Bismark Amoh
Akash Tarkunde
Katy F Zhu
Matthew Avalos
Eric B Dammer
Duc M Duong
Nicholas T Seyfried
Joshua M Shulman
Ismael Al-Ramahi
Juan Botas

Publication Date

3-11-2025

Journal

npj Parkinson's Disease

DOI

10.1038/s41531-025-00899-z

PMID

40069190

PMCID

PMC11897226

PubMedCentral® Posted Date

3-10-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Genetics, Computational biology and bioinformatics

Abstract

Parkinson's disease (PD) starts decades before symptoms appear, usually in the later decades of life, when age-related changes are occurring. To identify molecular changes early in the disease course and distinguish PD pathologies from aging, we generated Drosophila expressing alpha-synuclein (αSyn) in neurons and performed longitudinal bulk transcriptomics and proteomics on brains at six time points across the lifespan and compared the data to healthy control flies as well as human post-mortem brain datasets. We found that translational and energy metabolism pathways were downregulated in αSyn flies at the earliest timepoints; comparison with the aged control flies suggests that elevated αSyn accelerates changes associated with normal aging. Unexpectedly, single-cell analysis at a mid-disease stage revealed that neurons upregulate protein synthesis and nonsense-mediated decay, while glia drive their overall downregulation. Longitudinal multi-omics approaches in animal models can thus help elucidate the molecular cascades underlying neurodegeneration vs. aging and co-pathologies.