TY - JOUR
T1 - Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS
AU - Prudencio, Mercedes
AU - Belzil, Veronique V.
AU - Batra, Ranjan
AU - Ross, Christian A.
AU - Gendron, Tania F.
AU - Pregent, Luc J.
AU - Murray, Melissa E.
AU - Overstreet, Karen K.
AU - Piazza-Johnston, Amelia E.
AU - Desaro, Pamela
AU - Bieniek, Kevin F.
AU - DeTure, Michael
AU - Lee, Wing C.
AU - Biendarra, Sherri M.
AU - Davis, Mary D.
AU - Baker, Matthew C.
AU - Perkerson, Ralph B.
AU - Van Blitterswijk, Marka
AU - Stetler, Caroline T.
AU - Rademakers, Rosa
AU - Link, Christopher D.
AU - Dickson, Dennis W.
AU - Boylan, Kevin B.
AU - Li, Hu
AU - Petrucelli, Leonard
N1 - Funding Information:
The C9orf72 repeat expansion accounts for approximately 34% of fALS cases and 6% of sALS cases4. Several pathological mechanisms have been postulated for c9ALS, including RNA toxicity resulting from the accumulation of repeat-containing transcripts (r(G4C2)exp and r(G2C4)exp) bidirectionally transcribed from the C9orf72 expansion. Both r(G4C2)exp and r(G2C4)exp are subject to repeat-associated non-ATG (RAN) translation, which leads to the production of dipeptide-repeat (DPR) proteins5–8. Inclusions immunopositive for these DPR proteins are numerous in cerebellum, neocortical regions and hippocampus of subjects with c9ALS, and several studies have shown evidence of their toxicity9–15, including a potential effect on RNA biogenesis12. r(G4C2)exp and r(G2C4)exp may also contribute to neurodegenera-tion through the formation of nuclear RNA foci that sequester, and cause loss of function of, key RNA-binding proteins16–20(RBPs). Several RBPs, including adenosine deaminase RNA-specific B2 (ADARB2) and hnRNPH1, colocalize with RNA foci in c9ALS brain tissues and/or neurons differentiated from induced pluripotent stem cells16,19,20. The impaired ability of RBPs to regulate their targets and the resulting defects in RNA processing are putative contributors to c9ALS pathogenesis. This notion is supported by the fact that misregulated RNA processing is widely implicated in ALS. For instance, cytoplasmic inclusions of transactive response DNA-binding protein 43 kDa (TDP-43) are present in the majority of ALS cases21, and mislocalization of TDP-43 from the nucleus to the cytoplasm is believed to result in misregulated splicing of TDP-43 RNA targets22. Additionally, ALS-associated mutations have been identified in several RBP-encoding genes, including TARDBP23 (encoding TDP-43), fused in sarcoma (FUS)24,25, ataxin 2 (ATXN2)26, EWS RNA-binding protein 1 (EWSR1)27, TAF15 RNA polymerase II (TAF15)28, HNRNPA1 and HNRNPA2B1 (ref. 29). Given the growing body of evidence that the C9orf72 repeat expansion, by virtue of foci and/or DPR proteins, results in aberrant RNA processing, we sought to investigate alterations in the c9ALS transcriptome.
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© 2015 Nature America, Inc. All rights reserved.
PY - 2015/8/30
Y1 - 2015/8/30
N2 - 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.
AB - 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.
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U2 - 10.1038/nn.4065
DO - 10.1038/nn.4065
M3 - Article
C2 - 26192745
AN - SCOPUS:84938421758
SN - 1097-6256
VL - 18
SP - 1175
EP - 1182
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 8
ER -