<i>C9ORF72</i>
            repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits

Chew, Jeannie; Gendron, Tania F.; Prudencio, Mercedes; Sasaguri, Hiroki; Zhang, Yong Jie; Castanedes‐Casey, Monica; Lee, Chris W.; Jansen-West, Karen; Kurti, Aishe; Murray, Melissa E.; Bieniek, Kevin F.; Bauer, Peter; Whitelaw, Ena C.; Rousseau, Linda; Stankowski, Jeannette N.; Stetler, Caroline; Daughrity, Lillian M.; Perkerson, Emilie A.; Desaro, Pamela; Johnston, Amelia; Overstreet, Karen; Edbauer, Dieter; Rademakers, Rosa; Boylan, Kevin B.; Dickson, Dennis W.; Fryer, John Denis; Petrucelli, Leonard

doi:10.1126/science.aaa9344

Cited by 347 publications

(382 citation statements)

References 34 publications

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“…In contrast, mice overexpressing the hexanucleotide expansion developed a motor neuron syndrome accompanied by the same pathological hallmarks as observed in C9 ALS patients [7,32]. 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: 97%

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: Electronic Supplementary Materialsmentioning

confidence: 97%

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

et al. 2018

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“…Assessment of α CAR IGF‐1 LV dose escalation and application of treatment at disease onset in this and new rodent models of disease48 will provide further information as to the extent of the therapeutic efficacy that can be achieved with this targeted therapeutic vector in ALS. Combinatorial gene therapy utilizing multicistronic LV vectors expressing additional factors, such as heat shock proteins49 or miR‐206,50 could further enhance the potency of this approach.…”

Section: Discussionmentioning

confidence: 99%

αCAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice

Eleftheriadou

Manolaras

Irvine

et al. 2016

Ann Clin Transl Neurol

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ObjectiveWe have previously described the generation of coxsackievirus and adenovirus receptor (α CAR)‐targeted vector, and shown that intramuscular delivery in mouse leg muscles resulted in specific retrograde transduction of lumbar‐motor neurons (MNs). Here, we utilized the α CAR‐targeted vector to investigate the in vivo neuroprotective effects of lentivirally expressed IGF‐1 for inducing neuronal survival and ameliorating the neuropathology and behavioral phenotypes of the SOD1G93A mouse model of ALS.MethodsWe produced cell factories of IGF‐1 expressing lentiviral vectors (LVs) bearing α CAR or Vesicular Stomatitis Virus glycoprotein (VSV‐G) on their surface so as to compare neuroprotection from MN transduced versus muscle transduced cells. We performed intramuscular delivery of either α CAR IGF‐1 or VSVG IGF‐1 LVs into key muscles of SOD1G93A mice prior to disease onset at day 28. Motor performance, coordination and gait analysis were assessed weekly.ResultsWe observed substantial therapeutic efficacy only with the α CAR IGF‐1 LV pretreatment with up to 50% extension of survival compared to controls. α CAR IGF‐1 LV‐treated animals retained muscle tone and had better motor performance during their prolonged survival. Histological analysis of spinal cord samples at end‐stage further confirmed that α CAR IGF‐1 LV treatment delays disease onset by increasing MN survival compared with age‐matched controls. Intrastriatal injection of α CAR eGFP LV in rats leads to transduction of neurons and glia locally and neurons in olfactory bulb distally.InterpretationOur data are indicative of the efficacy of the α CAR IGF‐1 LV in this model and support its candidacy for early noninvasive neuroprotective therapy in ALS.

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“…Our group has previously investigated the dietary administration of cycad flour or extracted sterol glucosides as causative agents in the purported disease cascade (91)(92)(93) On account of our increased understanding of the underlying genetic causal factors at play in ALS (Figure 1), there have been multiple additional murine models developed since the advent of the mutant SOD1 mouse. These include mice expressing mutant TDP-43 or the C9ORF72-associated hexanucleotide repeat expansions (95)(96)(97). Characterising these additional systems allow for a more representative model of the overall ALS population as it takes into account the multiple underlying pathological changes that are implicated in disease pathogenesis.…”

Section: Development Of Alternate Models To More Effectively Mirror Tmentioning

confidence: 99%

Disparity of outcomes: the limits of modeling amyotrophic lateral sclerosis in murine models and translating results clinically

Zwiegers

Shaw

2015

jcbmr

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Amyotrophic lateral sclerosis (ALS) is a devastatingly progressive neurodegenerative disorder with multiple underlying etiological factors contributing to disease pathogenesis. Despite intensive research efforts and therapeutic development, disease presentation in ALS remains largely intractable to intervention. To date, the most common rodent model used in preclinical drug development accounts for a small proportion of the affected patient population and is predicated upon the significant overexpression of a mutant form of the human antioxidant protein, superoxide dismutase 1 (mSOD1). After more than 50 clinical trials, there is an alarming paucity of positive outcomes at the clinical level of ALS therapeutics with strong supporting pre-clinical data in mSOD1 models. Potential reasons for the negative clinical results are multifactorial in nature and include an overly reductionist model system that is heavily influenced by individual transgene level variation, as well as attempting to widely apply findings derived from a model of specific genetic causality to a patient population where the majority of cases are of unknown etiology. With such a tremendous disease burden and a lack of therapeutic options, it is critical that the research community re-evaluate the dependence on mSOD1 pre-clinical models as the gold standard prior to translating findings at the clinical level. Here we briefly review both the clinical and pre-clinical findings of select therapeutics, discuss the limitations of pre-clinical mSOD1 models, and suggest future stratagems that could aid in the clinical translation of efficacious therapeutic agents.

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C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits

Cited by 347 publications

References 34 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

αCAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice

Disparity of outcomes: the limits of modeling amyotrophic lateral sclerosis in murine models and translating results clinically

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