title: Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers.
abstract: 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.
authors.affiliation: 1 Department of Neurology, Ulm University, Ulm, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Freischmidt
authors.affiliation: 1 Department of Neurology, Ulm University, Ulm, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Müller
authors.affiliation: 1 Department of Neurology, Ulm University, Ulm, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zondler
authors.affiliation: 1 Department of Neurology, Ulm University, Ulm, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Weydt
authors.affiliation: 2 Institute of Human Genetics, Ulm University, Ulm, Germany.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Volk
authors.affiliation: 3 Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Anže Lošdorfer
authors.initials: AL
authors.lastname: Božič
authors.affiliation: 4 Department of Medical Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Walter
authors.affiliation: 4 Department of Medical Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.affiliation: 5 Institute for Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mayer
authors.affiliation: 1 Department of Neurology, Ulm University, Ulm, Germany.
authors.forename: Christine A F
authors.initials: CA
authors.lastname: von Arnim
authors.affiliation: 1 Department of Neurology, Ulm University, Ulm, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Otto
authors.affiliation: 3 Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Dieterich
authors.affiliation: 6 Genomics-Core Facility, University Hospital Ulm, Centre for Biomedical Research, Ulm, Germany.
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Holzmann
authors.affiliation: 1 Department of Neurology, Ulm University, Ulm, Germany 7 The Institute of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden 8 Virtual Helmholtz Institute RNA dysmetabolism in Amyotrophic Lateral Sclerosis and Fronto-temporal Dementia, Germany.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.affiliation: 1 Department of Neurology, Ulm University, Ulm, Germany 8 Virtual Helmholtz Institute RNA dysmetabolism in Amyotrophic Lateral Sclerosis and Fronto-temporal Dementia, Germany.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: 1 Department of Neurology, Ulm University, Ulm, Germany.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Danzer
authors.affiliation: 1 Department of Neurology, Ulm University, Ulm, Germany jochen.weishaupt@uni-ulm.de.
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000235:genetics*; D000073885:C9orf72 Protein; D015536:Down-Regulation; D006579:Heterozygote; D006801:Humans; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D046228:Microarray Analysis; D009154:Mutation / Q000235:genetics; D062706:Prodromal Symptoms; D011506:Proteins / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D035683:MicroRNAs; D011506:Proteins; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: C9ORF72; SOD1; amyotrophic lateral sclerosis; microRNA; mutation carriers