TY - JOUR
T1 - Deep sequencing of sncRNAs reveals hallmarks and regulatory modules of the transcriptome during Parkinson’s disease progression
AU - Kern, Fabian
AU - Fehlmann, Tobias
AU - Violich, Ivo
AU - Alsop, Eric
AU - Hutchins, Elizabeth
AU - Kahraman, Mustafa
AU - Grammes, Nadja L.
AU - Guimarães, Pedro
AU - Backes, Christina
AU - Poston, Kathleen L.
AU - Casey, Bradford
AU - Balling, Rudi
AU - Geffers, Lars
AU - Krüger, Rejko
AU - Galasko, Douglas
AU - Mollenhauer, Brit
AU - Meese, Eckart
AU - Wyss-Coray, Tony
AU - Craig, David W.
AU - Van Keuren-Jensen, Kendall
AU - Keller, Andreas
N1 - Funding Information:
PPMI, a public-private partnership, is funded by the Michael J. Fox Foundation (MJFF) for Parkinson’s Research and funding partners, including Abbvie, Allergan, Amathus Therapeutics, Avid, Biogen, BioLegend, Bristol-Myers Squibb, Celgene, Denali, GE Healthcare, Genetech, GlaxoSmithKline, Handl Therapeutics, Insitro, Janssen Neuroscience, Lilly, Lundbeck, Merck, MSD, Pfizer, Piramal, Prevail, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, Verily, Voyager and Golub Capital. We highly appreciate the encouragement and support of K. Nikolich in setting up and performing the study. We thank S. Levy and N. Prasad at the HudsonAlpha Institute for Biotechnology for adapting the small RNA sequencing protocol to the instruments and platforms used and performing the sequencing experiments. The microarray experiments were performed as fee-for-service by Hummingbird Diagnostics. We acknowledge the support of HbDx. We give special thanks to all participating patients in the study. Additionally, we are very grateful for all received funding and private donations that enabled us to carry out the project. Furthermore, we acknowledge the joint effort of the NCER-PD consortium members generally contributing to the Luxembourg Parkinson’s Study. The study is funded by the MJFF for Parkinson’s Research under reference 14446 and by the Schaller-Nikolich Foundation.
Funding Information:
PPMI, a public-private partnership, is funded by the Michael J. Fox Foundation (MJFF) for Parkinson’s Research and funding partners, including Abbvie, Allergan, Amathus Therapeutics, Avid, Biogen, BioLegend, Bristol-Myers Squibb, Celgene, Denali, GE Healthcare, Genetech, GlaxoSmithKline, Handl Therapeutics, Insitro, Janssen Neuroscience, Lilly, Lundbeck, Merck, MSD, Pfizer, Piramal, Prevail, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, Verily, Voyager and Golub Capital. We highly appreciate the encouragement and support of K. Nikolich in setting up and performing the study. We thank S. Levy and N. Prasad at the HudsonAlpha Institute for Biotechnology for adapting the small RNA sequencing protocol to the instruments and platforms used and performing the sequencing experiments. The microarray experiments were performed as fee-for-service by Hummingbird Diagnostics. We acknowledge the support of HbDx. We give special thanks to all participating patients in the study. Additionally, we are very grateful for all received funding and private donations that enabled us to carry out the project. Furthermore, we acknowledge the joint effort of the NCER-PD consortium members generally contributing to the Luxembourg Parkinson’s Study. The study is funded by the MJFF for Parkinson’s Research under reference 14446 and by the Schaller-Nikolich Foundation.
Funding Information:
The authors declare the following competing interests: E.H. received funding from the MJFF; M.K. is employed by Hummingbird Diagnostics; K.L.P. is a member of the executive steering committee of PPMI and received funding from the MJFF; B.C. is an Associate Director in MJFF’s Research Programs division and employed by the MJFF; B.M. is a member of the executive steering committee of PPMI and principal investigator of the Systemic Synuclein Sampling Study of the MJFF; T.W.C. is a founder and scientific advisor of Alkahest; D.W.C. and K.V.K.-J. received funding from MJFF and are principal investigators of RNA bioinformatics at PPMI; A.K. received funding from the MJFF.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. part of Springer Nature.
PY - 2021/3/15
Y1 - 2021/3/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85110402243&partnerID=8YFLogxK
U2 - 10.1038/s43587-021-00042-6
DO - 10.1038/s43587-021-00042-6
M3 - Article
SN - 2662-8465
VL - 1
SP - 309
EP - 322
JO - Nature Aging
JF - Nature Aging
IS - 3
ER -