Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS

Topic: Brain proteins, microglia and lab models

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders with clinical, genetic, and neuropathological overlap. A hexanucleotide (GGGGCC) repeat expansion in a non-coding region of C9ORF72 is the major genetic cause of both diseases. The mechanisms by which this repeat expansion causes "c9FTD/ALS" are not definitively known, but RNA-mediated toxicity is a likely culprit. RNA transcripts of the expanded GGGGCC repeat form nuclear foci in c9FTD/ALS, and also undergo repeat-associated non-ATG (RAN) translation resulting in the production of three aggregation-prone proteins. The goal of this study was to examine whether antisense transcripts resulting from bidirectional transcription of the expanded repeat behave in a similar manner. We show that ectopic expression of (CCCCGG)66 in cultured cells results in foci formation. Using novel polyclonal antibodies for the detection of possible (CCCCGG)exp RAN proteins [poly(PR), poly(GP) and poly(PA)], we validated that (CCCCGG)66 is also subject to RAN translation in transfected cells. Of importance, foci composed of antisense transcripts are observed in the frontal cortex, spinal cord and cerebellum of c9FTD/ALS cases, and neuronal inclusions of poly(PR), poly(GP) and poly(PA) are present in various brain tissues in c9FTD/ALS, but not in other neurodegenerative diseases, including CAG repeat disorders. Of note, RNA foci and poly(GP) inclusions infrequently co-occur in the same cell, suggesting these events represent two distinct ways in which the C9ORF72 repeat expansion may evoke neurotoxic effects. These findings provide mechanistic insight into the pathogenesis of c9FTD/ALS, and have significant implications for therapeutic strategies.

Key findings

• We show that ectopic expression of (CCCCGG)66 in cultured cells results in foci formation.
• These findings provide mechanistic insight into the pathogenesis of c9FTD/ALS, and have significant implications for therapeutic strategies.

Why it matters

This study found that the antisense strand of the expanded C9ORF72 repeat forms RNA clumps and produces three proteins in cells and in brain tissue from people with c9FTD/ALS. It identifies possible disease mechanisms but does not test a therapy or show benefit in patients.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1007/s00401-013-1192-8
• PubMed: 24129584
• Original source →
• Free full text: Acta Neuropathologica →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{gendron2013-24129584,
  author  = {Gendron, T. F. and Bieniek, K. F. and Zhang, Y. J. and Jansen-West, K. and Ash, P. E. and Caulfield, T. and Daughrity, L. and Dunmore, J. H. and others},
  title   = {{Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS}},
  journal = {Acta neuropathologica},
  year    = {2013},
  doi     = {10.1007/s00401-013-1192-8},
  pmid    = {24129584},
  url     = {https://doi.org/10.1007/s00401-013-1192-8}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD Neuron · 2011-09-21 · usefulness score 63/100 · Lewy body dementia
• Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS Neuron · 2011-09-21 · usefulness score 62/100 · Lewy body dementia
• A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study The Lancet. Neurology · 2011-12-07 · usefulness score 61/100 · Lewy body dementia
• Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics Brain : a journal of neurology · 2012-03-01 · usefulness score 60/100 · Getting a diagnosis
• The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS Science (New York, N.Y.) · 2013-02-07 · usefulness score 59/100 · Lewy body dementia
• Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS Neuron · 2013-02-12 · usefulness score 57/100 · Lewy body dementia
• Are amyotrophic lateral sclerosis patients cognitively normal? Neurology · 2003-04-01 · usefulness score 54/100 · Getting a diagnosis
• The role of tau in neurodegeneration Molecular neurodegeneration · 2009-03-11 · usefulness score 52/100 · Lewy body dementia
• Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72 Acta neuropathologica · 2011-11-15 · usefulness score 51/100 · Brain tissue and pathology
• Cognitive impairment in amyotrophic lateral sclerosis The Lancet. Neurology · 2007-11-01 · usefulness score 50/100 · Lewy body dementia

Later studies that cite this one

25 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• Amyotrophic lateral sclerosis Lancet (London, England) · 2017-05-25 · usefulness score 59/100 · Lewy body dementia
• Frontotemporal dementia Lancet (London, England) · 2015-10-01 · usefulness score 59/100 · Getting a diagnosis
• C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins Nature neuroscience · 2016-03-21 · usefulness score 58/100 · Brain tissue and pathology
• GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport Nature · 2015-08-26 · usefulness score 58/100 · Lewy body dementia
• C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins Science (New York, N.Y.) · 2014-08-07 · usefulness score 58/100 · Lewy body dementia
• Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits Science (New York, N.Y.) · 2015-05-14 · usefulness score 57/100 · Lewy body dementia
• The frontotemporal dementia-motor neuron disease continuum Lancet (London, England) · 2016-03-14 · usefulness score 56/100 · Getting a diagnosis
• C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles Cell · 2016-10-01 · usefulness score 54/100 · Lewy body dementia

Related studies in Lewy body dementia

• RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia Proceedings of the National Academy of Sciences of the United States of America · 2013-11-18 · usefulness score 57/100
• Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins Acta neuropathologica · 2013-10-17 · usefulness score 54/100
• Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic Cell reports · 2013-11-27 · usefulness score 55/100
• Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death Neuron · 2014-12-01 · usefulness score 52/100
• Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration Proceedings of the National Academy of Sciences of the United States of America · 2013-10-29 · usefulness score 53/100
• Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion Science translational medicine · 2013-10-01 · usefulness score 53/100

Similar studies

• Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs 2016 · Lewy body dementia
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