Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS

• Published in: Nature neuroscience Vol. 18; no. 8; pp. 1175 - 1182
• Main Authors: Prudencio, Mercedes, Belzil, Veronique V, Batra, Ranjan, Ross, Christian A, Gendron, Tania F, Pregent, Luc J, Murray, Melissa E, Overstreet, Karen K, Piazza-Johnston, Amelia E, Desaro, Pamela, Bieniek, Kevin F, DeTure, Michael, Lee, Wing C, Biendarra, Sherri M, Davis, Mary D, Baker, Matthew C, Perkerson, Ralph B, van Blitterswijk, Marka, Stetler, Caroline T, Rademakers, Rosa, Link, Christopher D, Dickson, Dennis W, Boylan, Kevin B, Li, Hu, Petrucelli, Leonard
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-08-2015; Nature Publishing Group
• Subjects: 38/91; 631/378/1689/1285; 631/378/2583; Adult; Aged; Alternative Splicing; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Analysis; Animal Genetics and Genomics; Behavioral Sciences; Biological Techniques; Biomedicine; C9orf72 Protein; Cerebellum - metabolism; Development and progression; Frontal Lobe - metabolism; Gene expression; Gene Expression Regulation - genetics; Genetic aspects; Genetic Association Studies; Genetic transcription; Health aspects; Heterogeneous-Nuclear Ribonucleoprotein Group F-H - metabolism; Humans; Middle Aged; Mutation; Neurobiology; Neuropathology; Neurosciences; Open reading frames; Physiological aspects; Polyadenylation - genetics; Properties; Proteins; Proteins - genetics; resource; RNA - metabolism; RNA polymerase; RNA splicing; Sequence Analysis, RNA; Transcriptome - genetics; Florida; United States > US; Minnesota
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.4065

Evidence suggests that aberrant RNA processing contributes to amyotrophic lateral sclerosis (ALS). Using RNA sequencing, Prudencio
et al
. assessed the extent of transcriptome defects in
C9orf72
-associated (c9ALS) and sporadic ALS (sALS) brains. They report extensive defects in expression, alternative splicing and alternative polyadenylation that are significantly distinct between individuals with c9ALS and sALS.
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.