RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia

Tao Zu, Yuanjing Liu, Monica Bañez-Coronel, Tammy Reid, Olga Pletnikova, Jada Lewis, Timothy M. Miller, Matthew B. Harms, Annet E. Falchook, S. H. Subramony, Lyle Ostrow, Jeffrey D Rothstein, Juan C Troncoso, Laura P W Ranum

Research output: Contribution to journalArticle

Abstract

The finding that a GGGGCC (G4C2) hexanucleotide repeat expansion in the chromosome 9 ORF 72 (C9ORF72) gene is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) links ALS/FTD to a large group of unstable microsatellite diseases. Previously, we showed that microsatellite expansion mutations can be bidirectionally transcribed and that these mutations express unexpected proteins by a unique mechanism, repeat-associated non-ATG (RAN) translation. In this study, we show that C9ORF72 antisense transcripts are elevated in the brains of C9ORF72 expansion-positive [C9(+)] patients, and antisense GGCCCC (G2C 4) repeat-expansion RNAs accumulate in nuclear foci in brain. Additionally, sense and antisense foci accumulate in blood and are potential biomarkers of the disease. Furthermore, we show that RAN translation occurs from both sense and antisense expansion transcripts, resulting in the expression of six RAN proteins (antisense: Pro-Arg, Pro-Ala, Gly-Pro; and sense: Gly-Ala, Gly-Arg, Gly-Pro). These proteins accumulate in cytoplasmic aggregates in affected brain regions, including the frontal and motor cortex, hippocampus, and spinal cord neurons, with some brain regions showing dramatic RAN protein accumulation and clustering. The finding that unique antisense G 2C4 RNA foci and three unique antisense RAN proteins accumulate in patient tissues indicates that bidirectional transcription of expanded alleles is a fundamental pathologic feature of C9ORF72 ALS/FTD. Additionally, these findings suggest the need to test therapeutic strategies that target both sense and antisense RNAs and RAN proteins in C9ORF72 ALS/FTD, and to more broadly consider the role of antisense expression and RAN translation across microsatellite expansion diseases.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number51
DOIs
StatePublished - Dec 17 2013

Fingerprint

Antisense RNA
Chromosomes, Human, Pair 9
Open Reading Frames
Microsatellite Repeats
Proteins
Brain
prolylarginine
N-glycylalanine
glycylproline
RNA
Mutation
Motor Cortex
Frontal Lobe
Cluster Analysis
Frontotemporal Dementia With Motor Neuron Disease
Hippocampus
Spinal Cord
Biomarkers
Alleles
Neurons

Keywords

  • Clustered aggregates
  • Cytoplasmic inclusions
  • Noncoding RNA

ASJC Scopus subject areas

  • General

Cite this

RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. / Zu, Tao; Liu, Yuanjing; Bañez-Coronel, Monica; Reid, Tammy; Pletnikova, Olga; Lewis, Jada; Miller, Timothy M.; Harms, Matthew B.; Falchook, Annet E.; Subramony, S. H.; Ostrow, Lyle; Rothstein, Jeffrey D; Troncoso, Juan C; Ranum, Laura P W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 51, 17.12.2013.

Research output: Contribution to journalArticle

Zu, Tao ; Liu, Yuanjing ; Bañez-Coronel, Monica ; Reid, Tammy ; Pletnikova, Olga ; Lewis, Jada ; Miller, Timothy M. ; Harms, Matthew B. ; Falchook, Annet E. ; Subramony, S. H. ; Ostrow, Lyle ; Rothstein, Jeffrey D ; Troncoso, Juan C ; Ranum, Laura P W. / RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 51.
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AU - Zu, Tao

AU - Liu, Yuanjing

AU - Bañez-Coronel, Monica

AU - Reid, Tammy

AU - Pletnikova, Olga

AU - Lewis, Jada

AU - Miller, Timothy M.

AU - Harms, Matthew B.

AU - Falchook, Annet E.

AU - Subramony, S. H.

AU - Ostrow, Lyle

AU - Rothstein, Jeffrey D

AU - Troncoso, Juan C

AU - Ranum, Laura P W

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AB - The finding that a GGGGCC (G4C2) hexanucleotide repeat expansion in the chromosome 9 ORF 72 (C9ORF72) gene is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) links ALS/FTD to a large group of unstable microsatellite diseases. Previously, we showed that microsatellite expansion mutations can be bidirectionally transcribed and that these mutations express unexpected proteins by a unique mechanism, repeat-associated non-ATG (RAN) translation. In this study, we show that C9ORF72 antisense transcripts are elevated in the brains of C9ORF72 expansion-positive [C9(+)] patients, and antisense GGCCCC (G2C 4) repeat-expansion RNAs accumulate in nuclear foci in brain. Additionally, sense and antisense foci accumulate in blood and are potential biomarkers of the disease. Furthermore, we show that RAN translation occurs from both sense and antisense expansion transcripts, resulting in the expression of six RAN proteins (antisense: Pro-Arg, Pro-Ala, Gly-Pro; and sense: Gly-Ala, Gly-Arg, Gly-Pro). These proteins accumulate in cytoplasmic aggregates in affected brain regions, including the frontal and motor cortex, hippocampus, and spinal cord neurons, with some brain regions showing dramatic RAN protein accumulation and clustering. The finding that unique antisense G 2C4 RNA foci and three unique antisense RAN proteins accumulate in patient tissues indicates that bidirectional transcription of expanded alleles is a fundamental pathologic feature of C9ORF72 ALS/FTD. Additionally, these findings suggest the need to test therapeutic strategies that target both sense and antisense RNAs and RAN proteins in C9ORF72 ALS/FTD, and to more broadly consider the role of antisense expression and RAN translation across microsatellite expansion diseases.

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