Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS

Mercedes Prudencio; Veronique V. Belzil; Ranjan Batra; Christian A. Ross; Tania F. Gendron; Luc J. Pregent; Melissa E. Murray; Karen K. Overstreet; Amelia E. Piazza-Johnston; Pamela Desaro; Kevin F. Bieniek; Michael DeTure; Wing C. Lee; Sherri M. Biendarra; Mary D. Davis; Matthew C. Baker; Ralph B. Perkerson; Marka Van Blitterswijk; Caroline T. Stetler; Rosa Rademakers; Christopher D. Link; Dennis W. Dickson; Kevin B. Boylan; Hu Li; Leonard Petrucelli

doi:10.1038/nn.4065

Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS

Mercedes Prudencio, Veronique V. Belzil, Ranjan Batra, Christian A. Ross, Tania F. Gendron, Luc J. Pregent, Melissa E. Murray, Karen K. Overstreet, Amelia E. Piazza-Johnston, Pamela Desaro, Kevin F. Bieniek, Michael DeTure, Wing C. Lee, Sherri M. Biendarra, Mary D. Davis, Matthew C. Baker, Ralph B. Perkerson, Marka Van Blitterswijk, Caroline T. Stetler, Rosa RademakersChristopher D. Link, Dennis W. Dickson, Kevin B. Boylan, Hu Li, Leonard Petrucelli

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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.

Original language	English (US)
Pages (from-to)	1175-1182
Number of pages	8
Journal	Nature Neuroscience
Volume	18
Issue number	8
DOIs	https://doi.org/10.1038/nn.4065
State	Published - Aug 30 2015

ASJC Scopus subject areas

General Neuroscience

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Prudencio, M., Belzil, V. V., Batra, R., Ross, C. A., Gendron, T. F., Pregent, L. J., Murray, M. E., Overstreet, K. K., Piazza-Johnston, A. E., Desaro, P., Bieniek, K. F., DeTure, M., Lee, W. C., Biendarra, S. M., Davis, M. D., Baker, M. C., Perkerson, R. B., Van Blitterswijk, M., Stetler, C. T., ... Petrucelli, L. (2015). Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS. Nature Neuroscience, 18(8), 1175-1182. https://doi.org/10.1038/nn.4065

Prudencio, M , Belzil, VV, Batra, R, Ross, CA, Gendron, TF, Pregent, LJ, Murray, ME, Overstreet, KK, Piazza-Johnston, AE, Desaro, P, Bieniek, KF, DeTure, M, Lee, WC, Biendarra, SM, Davis, MD, Baker, MC, Perkerson, RB, Van Blitterswijk, M, Stetler, CT, Rademakers, R, Link, CD, Dickson, DW, Boylan, KB, Li, H & Petrucelli, L 2015, 'Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS', Nature Neuroscience, vol. 18, no. 8, pp. 1175-1182. https://doi.org/10.1038/nn.4065

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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.",

author = "Mercedes Prudencio and Belzil, {Veronique V.} and Ranjan Batra and Ross, {Christian A.} and Gendron, {Tania F.} and Pregent, {Luc J.} and Murray, {Melissa E.} and Overstreet, {Karen K.} and Piazza-Johnston, {Amelia E.} and Pamela Desaro and Bieniek, {Kevin F.} and Michael DeTure and Lee, {Wing C.} and Biendarra, {Sherri M.} and Davis, {Mary D.} and Baker, {Matthew C.} and Perkerson, {Ralph B.} and {Van Blitterswijk}, Marka and Stetler, {Caroline T.} and Rosa Rademakers and Link, {Christopher D.} and Dickson, {Dennis W.} and Boylan, {Kevin B.} and Hu Li and Leonard Petrucelli",

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AU - Desaro, Pamela

AU - Bieniek, Kevin F.

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AU - Lee, Wing C.

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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

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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.

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Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS

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