RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention

Donnelly, Christopher J.; Zhang, Ping-Wu; Pham, Jacqueline T.; Haeusler, Aaron R.; Mistry, Nipun A.; Vidensky, Svetlana; Daley, Elizabeth L.; Poth, Erin M.; Hoover, Benjamin; Fines, Daniel M.; Maragakis, Nicholas J.; Tienari, Pentti J.; Petrucelli, Leonard; Traynor, Bryan J.; Wang, Jiou; Rigo, Frank; Bennett, C. Frank; Blackshaw, Seth; Sattler, Rita; Rothstein, Jeffrey D.

doi:10.1016/j.neuron.2013.10.015

Cited by 808 publications

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“…Second, both sense and antisense repeat RNA were found to be mainly localized to the cytoplasm, both diffusely as well as in RNA foci. While in C9orf72 patients most RNA foci have been found to be located in the nucleus, cytoplasmic RNA foci have also been found in postmortem tissue [11,12,34], as well as in patient-derived cell cultures [17]. These data suggest that RNA toxicity might be mediated by cytoplasmic repeat RNA, which might explain why no correlation between extent of nuclear RNA foci and neurodegeneration has been found in postmortem tissue [15].…”

Section: Discussionmentioning

confidence: 90%

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A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

et al. 2018

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The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGG GCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine-arginine and proline-arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis of C9orf72-associated ALS/FTD.

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Section: Discussionmentioning

confidence: 90%

“…Furthermore, treatment of iPSC-derived neurons (iPSNs) from C9 patients with C9 antisense oligonucleotides at least partially corrected their phenotype, all suggesting a gain-of-function pathogenic mechanism [17,41].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

et al. 2018

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“…AMPAR changes have been demonstrated as a contributor in both in vitro and in vivo models of SOD1‐ALS (Van Damme et al, 2007), in vitro studies of C9orf72‐ALS (Donnelly et al, 2013), postmortem studies of sporadic ALS (Kwak, Hideyama, Yamashita, & Aizawa, 2010), and cell‐autonomous studies of FUS‐ALS (Udagawa et al, 2015). Motor neurons are known to be especially vulnerable to AMPA‐mediated excitotoxicity due to an unusually high density of Ca 2+ ‐permeable AMPA receptors and low calcium buffering ability (Palecek, Lips, & Keller, 1999; Vandenberghe et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Kia

McAvoy

Krishnamurthy

et al. 2018

Glia

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Mutations in fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting both upper and lower motor neurons. While it is established that astrocytes contribute to the death of motor neurons in ALS, the specific contribution of mutant FUS (mutFUS) through astrocytes has not yet been studied. Here, we used primary astrocytes expressing a N‐terminally GFP tagged R521G mutant or wild‐type FUS (WTFUS) and show that mutFUS‐expressing astrocytes undergo astrogliosis, damage co‐cultured motor neurons via activation of an inflammatory response and produce conditioned medium (ACM) that is toxic to motor neurons in isolation. Time lapse imaging shows that motor neuron cultures exposed to mutFUS ACM, but not WTFUS ACM, undergo significant cell loss, which is preceded by progressive degeneration of neurites. We found that Tumor Necrosis Factor‐Alpha (TNFα) is secreted into ACM of mutFUS‐expressing astrocytes. Accordingly, mutFUS astrocyte‐mediated motor neuron toxicity is blocked by targeting soluble TNFα with neutralizing antibodies. We also found that mutant astrocytes trigger changes to motor neuron AMPA receptors (AMPAR) that render them susceptible to excitotoxicity and AMPAR‐mediated cell death. Our data provide the first evidence of astrocytic involvement in FUS‐ALS, identify TNFα as a mediator of this toxicity, and provide several potential therapeutic targets to protect motor neurons in FUS‐linked ALS.

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“…Disease‐modifying therapies advancing toward clinical trials include antisense oligonucleotides (ASOs) and small molecules that target G 4 C 2 transcripts and consequently reduce G 4 C 2 RNA foci and DPR proteins in C9orf72 patient‐derived cell models and animal models 9, 10, 11, 12, 13. In parallel with the rapid development of these potential therapeutics, biomarkers that measure target engagement, disease onset, and disease progression must be established for clinical trials to be successful.…”

Section: Introductionmentioning

confidence: 99%

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Meeter

Gendron

Sias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72‐associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel‐wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72‐associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

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RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention

Cited by 808 publications

References 50 publications

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

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