2014
DOI: 10.1016/j.neuron.2014.12.010
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Antisense Proline-Arginine RAN Dipeptides Linked to C9ORF72-ALS/FTD Form Toxic Nuclear Aggregates that Initiate In Vitro and In Vivo Neuronal Death

Abstract: SUMMARY Expanded GGGGCC nucleotide repeats within the C9ORF72 gene are the most common genetic mutation associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Sense and antisense transcripts of these expansions are translated to form five dipeptide repeat proteins (DRPs). We employed primary cortical and motor neuron cultures, live-cell imaging, and transgenic fly models and found that the arginine-rich dipeptides, in particular Proline-Arginine (PR), are potently neurotoxi… Show more

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Cited by 496 publications
(726 citation statements)
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“…The first proposes that G4C2 repeat transcript as well as the antisense repeat transcript may accumulate in RNA foci which sequester RNA-binding proteins, leading to disturbed RNA metabolism that causes neurodegeneration [7][8][9] . The second hypothesis builds on observations that the long repeat gives rise to proteins consisting of dipeptides by non-ATG translation (RAN translation) 10 . These dipeptide repeat proteins can then aggregate and cause neurodegeneration in affected brain regions 11 .…”
Section: C9orf72 Interaction With Cofilin Modulates Actin Dynamics Inmentioning
confidence: 99%
See 1 more Smart Citation
“…The first proposes that G4C2 repeat transcript as well as the antisense repeat transcript may accumulate in RNA foci which sequester RNA-binding proteins, leading to disturbed RNA metabolism that causes neurodegeneration [7][8][9] . The second hypothesis builds on observations that the long repeat gives rise to proteins consisting of dipeptides by non-ATG translation (RAN translation) 10 . These dipeptide repeat proteins can then aggregate and cause neurodegeneration in affected brain regions 11 .…”
Section: C9orf72 Interaction With Cofilin Modulates Actin Dynamics Inmentioning
confidence: 99%
“…Loss of function is a possible pathomechanism as patients with C9ORF72 repeat expansion show a 50% reduction in mRNA levels of both long and short transcripts 2,3 . Recent studies revealed that reduction of C9ORF72 levels in both cortical and motoneurons does not affect cellular survival in vitro 10 or in vivo 12 . However, zebrafish models show reduced axon length in motoneurons and reduced locomotion after antisense morpholino-mediated reduction of C9ORF72 levels 5 .…”
Section: C9orf72 Interaction With Cofilin Modulates Actin Dynamics Inmentioning
confidence: 99%
“…A gain of toxic function hypothesis is also supported by the presence of repeat-associated non-ATG dependent translation (RAN translation) to generate dipeptide repeats (DPRs), which have been detected in C9orf72-ALS/FTD tissue [18,23]. It is known that RAN translation of the intronic GGGGCC C9orf72 repeat expansions in both sense and anti-sense directions can generate up to five different DPRs, which can be toxic [18,[23][24][25][26].…”
Section: Amyotrophic Lateral Sclerosis (Als) Also Commonly Known Asmentioning
confidence: 99%
“…Poly-PR and poly-GR seem to impair the biogenesis of ribosomal RNA [26] and poly-GA mediates cytotoxicity by endoplasmic reticulum stress, increased release of lactate dehydrogenase and caspase-3 activation [25]. A recent study has shown the arginine-rich DPRs are neurotoxic causing nuclear and nucleoli disruption, reduction in the number of processing bodies and formation of granules [24].…”
Section: Amyotrophic Lateral Sclerosis (Als) Also Commonly Known Asmentioning
confidence: 99%
“…The G 4 C 2 repeat is translated in all reading frames in both the sense and antisense strands, resulting in several different dipeptides that accumulate specifically within the cells of patients carrying pathogenic (>22) repeat lengths. These dipeptides are toxic to cells in vitro and in vivo [69,[136][137][138], causing cell death in some cases by disrupting RNA processing within nucleoli [69], or by altering the function of essential proteins such as Unc119 [137], a trafficking factor required for axon development [139]. Moreover, the sequestration of RNA binding proteins by expanded G 4 C 2 RNA may be synergistic with the toxicity induced by RAN translation products [138]: many of the proteins bound by G 4 C 2 RNA catalyze the nuclear export of RNA, potentially facilitating cytoplasmic RAN translation of expanded C9orf72 repeats and accentuating toxicity [121].…”
Section: Alternative Rna-based Mechanismsmentioning
confidence: 99%