Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers

TY - JOUR

T1 - Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers

AU - Freischmidt, Axel

AU - Müller, Kathrin

AU - Zondler, Lisa

AU - Weydt, Patrick

AU - Volk, Alexander E

AU - Božič, Anže Lošdorfer

AU - Walter, Michael

AU - Bonin, Michael

AU - Mayer, Benjamin

AU - von Arnim, Christine A F

AU - Otto, Markus

AU - Dieterich, Christoph

AU - Holzmann, Karlheinz

AU - Andersen, Peter M

AU - Ludolph, Albert C

AU - Danzer, Karin M

AU - Weishaupt, Jochen H

N1 - © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2014/11/1

Y1 - 2014/11/1

N2 - Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.

AB - Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.

KW - Adult

KW - Amyotrophic Lateral Sclerosis

KW - Down-Regulation

KW - Heterozygote

KW - Humans

KW - MicroRNAs

KW - Microarray Analysis

KW - Mutation

KW - Prodromal Symptoms

KW - Proteins

KW - Superoxide Dismutase

U2 - 10.1093/brain/awu249

DO - 10.1093/brain/awu249

M3 - SCORING: Journal article

C2 - 25193138

VL - 137

SP - 2938

EP - 2950

JO - BRAIN

JF - BRAIN

SN - 0006-8950

IS - 11

ER -