Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS.
Mercedes PrudencioVeronique V BelzilRanjan BatraChristian A RossTania F GendronLuc J PregentMelissa E MurrayKaren K OverstreetAmelia E Piazza-JohnstonPamela DesaroKevin F BieniekMichael DeTureWing C LeeSherri M BiendarraMary D DavisMatthew C BakerRalph B PerkersonMarka van BlitterswijkCaroline T StetlerRosa RademakersChristopher D LinkGourisankar GhoshKevin B BoylanHu LiLeonard PetrucelliPublished in: Nature neuroscience (2015)
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.
Keyphrases
- amyotrophic lateral sclerosis
- gene expression
- genome wide
- poor prognosis
- dna methylation
- machine learning
- risk assessment
- rna seq
- artificial intelligence
- transcription factor
- big data
- blood brain barrier
- resting state
- binding protein
- copy number
- deep learning
- late onset
- network analysis
- early onset
- functional connectivity