Deep sequencing of sncRNAs reveals hallmarks and regulatory modules of the transcriptome during Parkinson’s disease progression

Fabian Kern, Tobias Fehlmann, Ivo Violich, Eric Alsop, Elizabeth Hutchins, Mustafa Kahraman, Nadja L. Grammes, Pedro Guimarães, Christina Backes, Kathleen L. Poston, Bradford Casey, Rudi Balling, Lars Geffers, Rejko Krüger, Douglas Galasko, Brit Mollenhauer, Eckart Meese, Tony Wyss-Coray, David W. Craig, Kendall Van Keuren-JensenAndreas Keller*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)

Abstract

Noncoding RNAs have diagnostic and prognostic importance in Parkinson’s disease (PD). We studied circulating small noncoding RNAs (sncRNAs) in two large-scale longitudinal PD cohorts (Parkinson’s Progression Markers Initiative (PPMI) and Luxembourg Parkinson’s Study (NCER-PD)) and modeled their impact on the transcriptome. Sequencing of sncRNAs in 5,450 blood samples of 1,614 individuals in PPMI yielded 323 billion reads, most of which mapped to microRNAs but covered also other RNA classes such as piwi-interacting RNAs, ribosomal RNAs and small nucleolar RNAs. Dysregulated microRNAs associated with disease and disease progression occur in two distinct waves in the third and seventh decade of life. Originating predominantly from immune cells, they resemble a systemic inflammation response and mitochondrial dysfunction, two hallmarks of PD. Profiling 1,553 samples from 1,024 individuals in the NCER-PD cohort validated biomarkers and main findings by an independent technology. Finally, network analysis of sncRNA and transcriptome sequencing from PPMI identified regulatory modules emerging in patients with progressing PD.

Original languageEnglish
Pages (from-to)309-322
Number of pages14
JournalNature Aging
Volume1
Issue number3
DOIs
Publication statusPublished - 15 Mar 2021

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