Deep Sequencing of SncRNAs Reveals Hallmarks and Regulatory Modules of the Transcriptome During Parkinson's Disease Progression

Overview

Journal Nat Aging

Specialty Geriatrics

Date 2023 Apr 28

PMID 37118411

Authors

Fabian Kern

Tobias Fehlmann

Ivo Violich

Eric Alsop

Elizabeth Hutchins

Mustafa Kahraman

Nadja L Grammes

Pedro Guimaraes

Christina Backes

Kathleen L Poston

Bradford Casey

Rudi Balling

Lars Geffers

Rejko Kruger

Douglas Galasko

Brit Mollenhauer

Eckart Meese

Tony Wyss-Coray

David W Craig

Kendall Van Keuren-Jensen

Andreas Keller

Affiliations

Soon will be listed here.

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.

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References

DeWeerdt S . Parkinson's disease: 4 big questions. Nature. 2016; 538(7626):S17. DOI: 10.1038/538S17a. View

Kalia L, Lang A . Parkinson's disease. Lancet. 2015; 386(9996):896-912. DOI: 10.1016/S0140-6736(14)61393-3. View

Jankovic J . Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008; 79(4):368-76. DOI: 10.1136/jnnp.2007.131045. View

Hamza T, Zabetian C, Tenesa A, Laederach A, Montimurro J, Yearout D . Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet. 2010; 42(9):781-5. PMC: 2930111. DOI: 10.1038/ng.642. View

Klemann C, Martens G, Sharma M, Martens M, Isacson O, Gasser T . Integrated molecular landscape of Parkinson's disease. NPJ Parkinsons Dis. 2017; 3:14. PMC: 5460267. DOI: 10.1038/s41531-017-0015-3. View

Scherzer C, Eklund A, Morse L, Liao Z, Locascio J, Fefer D . Molecular markers of early Parkinson's disease based on gene expression in blood. Proc Natl Acad Sci U S A. 2007; 104(3):955-60. PMC: 1766335. DOI: 10.1073/pnas.0610204104. View

Li Y, Wong G, Humphrey J, Raj T . Prioritizing Parkinson's disease genes using population-scale transcriptomic data. Nat Commun. 2019; 10(1):994. PMC: 6397174. DOI: 10.1038/s41467-019-08912-9. View

Wang Q, Zhang Y, Wang M, Song W, Shen Q, McKenzie A . The landscape of multiscale transcriptomic networks and key regulators in Parkinson's disease. Nat Commun. 2019; 10(1):5234. PMC: 6868244. DOI: 10.1038/s41467-019-13144-y. View

Calligaris R, Banica M, Roncaglia P, Robotti E, Finaurini S, Vlachouli C . Blood transcriptomics of drug-naïve sporadic Parkinson's disease patients. BMC Genomics. 2015; 16:876. PMC: 4625854. DOI: 10.1186/s12864-015-2058-3. View

10.

Chen-Plotkin A . Parkinson disease: Blood transcriptomics for Parkinson disease?. Nat Rev Neurol. 2017; 14(1):5-6. PMC: 5831123. DOI: 10.1038/nrneurol.2017.166. View

11.

Wang C, Chen L, Yang Y, Zhang M, Wong G . Identification of potential blood biomarkers for Parkinson's disease by gene expression and DNA methylation data integration analysis. Clin Epigenetics. 2019; 11(1):24. PMC: 6371578. DOI: 10.1186/s13148-019-0621-5. View

12.

Hossein-Nezhad A, Pedram Fatemi R, Ahmad R, Peskind E, Zabetian C, Hu S . Transcriptomic Profiling of Extracellular RNAs Present in Cerebrospinal Fluid Identifies Differentially Expressed Transcripts in Parkinson's Disease. J Parkinsons Dis. 2016; 6(1):109-17. PMC: 4927907. DOI: 10.3233/JPD-150737. View

13.

Marz M, Ferracin M, Klein C . MicroRNAs as biomarker of Parkinson disease? Small but mighty. Neurology. 2015; 84(7):636-8. DOI: 10.1212/WNL.0000000000001275. View

14.

Starhof C, Hejl A, Heegaard N, Carlsen A, Burton M, Lilje B . The biomarker potential of cell-free microRNA from cerebrospinal fluid in Parkinsonian Syndromes. Mov Disord. 2018; 34(2):246-254. DOI: 10.1002/mds.27542. View

15.

Keller A, Leidinger P, Bauer A, ElSharawy A, Haas J, Backes C . Toward the blood-borne miRNome of human diseases. Nat Methods. 2011; 8(10):841-3. DOI: 10.1038/nmeth.1682. View

16.

Leidinger P, Backes C, Deutscher S, Schmitt K, Mueller S, Frese K . A blood based 12-miRNA signature of Alzheimer disease patients. Genome Biol. 2013; 14(7):R78. PMC: 4053778. DOI: 10.1186/gb-2013-14-7-r78. View

17.

Keller A, Backes C, Haas J, Leidinger P, Maetzler W, Deuschle C . Validating Alzheimer's disease micro RNAs using next-generation sequencing. Alzheimers Dement. 2016; 12(5):565-76. DOI: 10.1016/j.jalz.2015.12.012. View

18.

Ludwig N, Fehlmann T, Kern F, Gogol M, Maetzler W, Deutscher S . Machine Learning to Detect Alzheimer's Disease from Circulating Non-coding RNAs. Genomics Proteomics Bioinformatics. 2019; 17(4):430-440. PMC: 6943763. DOI: 10.1016/j.gpb.2019.09.004. View

19.

Valentine M, Hashimoto K, Fukuhara T, Saiki S, Ishikawa K, Hattori N . Multi-year whole-blood transcriptome data for the study of onset and progression of Parkinson's Disease. Sci Data. 2019; 6(1):20. PMC: 6472336. DOI: 10.1038/s41597-019-0022-9. View

20.

Lawton M, Baig F, Toulson G, Morovat A, Evetts S, Ben-Shlomo Y . Blood biomarkers with Parkinson's disease clusters and prognosis: The oxford discovery cohort. Mov Disord. 2019; 35(2):279-287. PMC: 7028059. DOI: 10.1002/mds.27888. View