title: Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS.
abstract: Increasing evidence suggests that defective RNA processing contributes to the development of amyotrophic lateral sclerosis (ALS). This may be especially true for ALS caused by a repeat expansion in C9orf72 (c9ALS), in which the accumulation of RNA foci and dipeptide-repeat proteins are expected to modify RNA metabolism. We report extensive alternative splicing (AS) and alternative polyadenylation (APA) defects in the cerebellum of c9ALS subjects (8,224 AS and 1,437 APA), including changes in ALS-associated genes (for example, ATXN2 and FUS), and in subjects with sporadic ALS (sALS; 2,229 AS and 716 APA). Furthermore, heterogeneous nuclear ribonucleoprotein H (hnRNPH) and other RNA-binding proteins are predicted to be potential regulators of cassette exon AS events in both c9ALS and sALS. Co-expression and gene-association network analyses of gene expression and AS data revealed divergent pathways associated with c9ALS and sALS.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Prudencio
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Veronique V
authors.initials: VV
authors.lastname: Belzil
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Ranjan
authors.identifier: 0000000266682505
authors.initials: R
authors.lastname: Batra
authors.affiliation: Information Technology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Luc J
authors.initials: LJ
authors.lastname: Pregent
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Melissa E
authors.identifier: 0000000173792545
authors.initials: ME
authors.lastname: Murray
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Overstreet
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Amelia E
authors.initials: AE
authors.lastname: Piazza-Johnston
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Desaro
authors.affiliation: 1] Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA. [2] Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Bieniek
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: DeTure
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Wing C
authors.initials: WC
authors.lastname: Lee
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Sherri M
authors.initials: SM
authors.lastname: Biendarra
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Mary D
authors.initials: MD
authors.lastname: Davis
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Baker
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Ralph B
authors.initials: RB
authors.lastname: Perkerson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Marka
authors.initials: M
authors.lastname: van Blitterswijk
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Caroline T
authors.initials: CT
authors.lastname: Stetler
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.affiliation: Integrative Physiology, Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Link
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Dennis W
authors.identifier: 0000000171897917
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Boylan
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000073885:C9orf72 Protein; D002531:Cerebellum / Q000378:metabolism*; D005625:Frontal Lobe / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D056726:Genetic Association Studies; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D026723:Polyadenylation / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D012313:RNA / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D059467:Transcriptome / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D011506:Proteins; D012313:RNA