Knock in of a hexanucleotide repeat expansion in the <i>C9orf72</i> gene induces ALS in rats

Dong, Wei; Zhang, Li; Sun, Caixian; Gao, Xiang; Guan, Feifei; Li, Jing; Chen, Wei; Ma, Yuanwu; Zhang, Lianfeng

doi:10.1002/ame2.12129

Cited by 15 publications

(14 citation statements)

References 38 publications

(103 reference statements)

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“…In the study by Zhu et al, they additionally documented that the same was true for cognitive deficits, neurodegeneration, glial activation, and accumulation of DPRs ( Zhu et al, 2020 ). Finally, a knock-in (KI) model was made in rats demonstrating the need of combining loss- and gain-of-function effects to cause FTD/ALS ( Dong et al, 2020b ). Eighty G 4 C 2 repeats with flanking fragments of human exons 1a and 1b were inserted in the rat C9orf72 locus, resulting in a 40% decrease of C9ORF72 protein expression in the brain and spinal cord of KI rats.…”

Section: C9orf72 Haploinsufficiency In Ftd/alsmentioning

confidence: 99%

C9ORF72: What It Is, What It Does, and Why It Matters

Smeyers

Banchi

Latouche

2021

Front. Cell. Neurosci.

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When the non-coding repeat expansion in the C9ORF72 gene was discovered to be the most frequent cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in 2011, this gene and its derived protein, C9ORF72, were completely unknown. The mutation appeared to produce both haploinsufficiency and gain-of-function effects in the form of aggregating expanded RNAs and dipeptide repeat proteins (DPRs). An unprecedented effort was then unleashed to decipher the pathogenic mechanisms and the functions of C9ORF72 in order to design therapies. A decade later, while the toxicity of accumulating gain-of-function products has been established and therapeutic strategies are being developed to target it, the contribution of the loss of function starts to appear more clearly. This article reviews the current knowledge about the C9ORF72 protein, how it is affected by the repeat expansion in models and patients, and what could be the contribution of its haploinsufficiency to the disease in light of the most recent findings. We suggest that these elements should be taken into consideration to refine future therapeutic strategies, compensating for the decrease of C9ORF72 or at least preventing a further reduction.

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Section: C9orf72 Haploinsufficiency In Ftd/alsmentioning

confidence: 99%

C9ORF72: What It Is, What It Does, and Why It Matters

Smeyers

Banchi

Latouche

2021

Front. Cell. Neurosci.

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“…On the other hand, the loss of C9ORF72 protein in rats requires the synergistic action of excitotoxicity to cause neuronal injury and disease progression. The ablation of C9ORF72 protein in rats and treatment with glutamate analogue kainic acid indeed stimulates the release of excitatory neurotransmitters resulting in an increased susceptibility of motor neurons to excitotoxicity, motor neuron degeneration and motor deficits [ 232 ].…”

Section: Modeling Als In Different Systemsmentioning

confidence: 99%

Where and Why Modeling Amyotrophic Lateral Sclerosis

Liguori

Amadio

Volonté

2021

IJMS

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Over the years, researchers have leveraged a host of different in vivo models in order to dissect amyotrophic lateral sclerosis (ALS), a neurodegenerative/neuroinflammatory disease that is heterogeneous in its clinical presentation and is multigenic, multifactorial and non-cell autonomous. These models include both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs and, more recently, non-human primates. Despite their obvious differences and peculiarities, only the concurrent and comparative analysis of these various systems will allow the untangling of the causes and mechanisms of ALS for finally obtaining new efficacious therapeutics. However, harnessing these powerful organisms poses numerous challenges. In this context, we present here an updated and comprehensive review of how eukaryotic unicellular and multicellular organisms that reproduce a few of the main clinical features of the disease have helped in ALS research to dissect the pathological pathways of the disease insurgence and progression. We describe common features as well as discrepancies among these models, highlighting new insights and emerging roles for experimental organisms in ALS.

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“…Recently, C9orf72 knock-in rats were generated by knocking in 80 G4C2 repeats with human flanking fragments within exon1a and exon1b at the rat C9orf72 locus. These rat models reduced C9orf72 protein expression in several CNS areas and showed motor deficits from four months of age due to motor neuron loss, thus being a further useful model for investigating the contributions of loss-of-function to neurotoxicity in C9orf72-related ALS [143].…”

Section: Rodents Carrying Chromosome 9 Open Reading Frame 72 (C9orf72) Mutationsmentioning

confidence: 99%

Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives

Bonifacino

Zerbo

Balbi

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS) is a fatal, multigenic, multifactorial, and non-cell autonomous neurodegenerative disease characterized by upper and lower motor neuron loss. Several genetic mutations lead to ALS development and many emerging gene mutations have been discovered in recent years. Over the decades since 1990, several animal models have been generated to study ALS pathology including both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs, and non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms at the basis of motor neuron degeneration and ALS progression, thus contributing to the development of new promising therapeutics. In this review, we describe the up to date and available ALS genetic animal models, classified by the different genetic mutations and divided per species, pointing out their features in modeling, the onset and progression of the pathology, as well as their specific pathological hallmarks. Moreover, we highlight similarities, differences, advantages, and limitations, aimed at helping the researcher to select the most appropriate experimental animal model, when designing a preclinical ALS study.

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Knock in of a hexanucleotide repeat expansion in the C9orf72 gene induces ALS in rats

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 15 publications

References 38 publications

C9ORF72: What It Is, What It Does, and Why It Matters

C9ORF72: What It Is, What It Does, and Why It Matters

Where and Why Modeling Amyotrophic Lateral Sclerosis

Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives

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