C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD

O’Rourke, Jacqueline G.; Bogdanik, Laurent; Muhammad, A.K.M. Ghulam; Gendron, Tania F.; Kim, Kevin J.; Austin, Andrew D.; Cady, Janet; Liu, Elaine Y.; Zarrow, Jonah E.; Grant, Sharday; Ho, Ritchie; Bell, Shaughn; Carmona, Sharon; Simpkinson, Megan; Lall, Deepti; Wu, Kathryn; Daughrity, Lillian M.; Dickson, Dennis W.; Harms, Matthew B.; Petrucelli, Leonard; Lee, Edward B.; Lutz, Cathleen; Baloh, Robert H.

doi:10.1016/j.neuron.2015.10.027

Cited by 267 publications

(323 citation statements)

References 36 publications

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“…Although it was not previously reported 58 , we observed significantly higher levels of GR+ punctae in hippocampal neurons in C9-BAC mice than controls (Fig. 6j) using a previously-validated poly(GR) antibody 11 .…”

Section: Small Molecule and Genetic Regulators Of Endosomal Traffickicontrasting

confidence: 52%

“…After permeabilization, the samples were equilibrated in 1x SSC buffer for 10 min at room temperature and then transferred into 50% formamide (2x SSC) for 10 min at 60°C. The repeat expansion-targeting probe and the negative control probe were ordered from Exiqon 58 . During this step, the probe mixture (1µl salmon sperm (10 µg/µl), 0.5 µl E. coli tRNA (20 µg/µl), 0.4 µl probe (25 µM), 25 µl 80% formamide/per sample) was made and placed at 95°C for at least 10 min.…”

Section: Methodsmentioning

confidence: 99%

“…To determine if Pikfyve inhibition rescues gain-of-function processes in vivo , we measured DPR levels in C9-BAC transgenic mice 58 with or without Apilimod treatment. Although it was not previously reported 58 , we observed significantly higher levels of GR+ punctae in hippocampal neurons in C9-BAC mice than controls (Fig.…”

Section: Small Molecule and Genetic Regulators Of Endosomal Traffickimentioning

confidence: 99%

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Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

Shi

Lin

Staats

et al. 2018

Nat Med

495

551

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Summary An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but its pathogenic mechanism remains unclear. Here we use human induced motor neurons (iMNs) to show that repeat-expanded C9ORF72 is haploinsufficient in ALS. We show that C9ORF72 interacts with endosomes and is required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduces C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms leads to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescues patient neuron survival and ameliorates neurodegenerative processes in both gain- and loss-of function C9ORF72 mouse models. Thus, modulating vesicle trafficking can rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN, and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS/FTD.

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Section: Small Molecule and Genetic Regulators Of Endosomal Traffickicontrasting

confidence: 52%

Section: Methodsmentioning

confidence: 99%

Section: Small Molecule and Genetic Regulators Of Endosomal Traffickimentioning

confidence: 99%

See 1 more Smart Citation

Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

Shi

Lin

Staats

et al. 2018

Nat Med

495

551

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“…Another formal test of loss- vs. gain-of-function involves the use of C9orf72 knockout mice and some of the recently described viral-mediated and BAC transgenic c9FTD/ALS models (Chew et al, 2015; O’Rourke et al, 2015; Peters et al, 2015). These models employ expression of human C9orf72 transgenes harboring various GGGGCC repeat lengths either via adeno-associated virus mediated somatic transgenesis (Chew et al, 2015) or in transgenic mice generated from a bacterial artificial chromosomes (BAC) that expresses a fragment of human C9orf72 containing an expanded hexanucleotide repeat (O’Rourke et al, 2015; Peters et al, 2015) or the full length C9orf72 gene harboring an expanded repeat (O’Rourke et al, 2015).…”

Section: Mechanism 1: Loss Of Functionmentioning

confidence: 99%

There has been an awakening: Emerging mechanisms of C9orf72 mutations in FTD/ALS

2016

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The discovery of C9orf72 mutations as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has awakened a surge of interest in deciphering how mutations in this mysterious gene cause disease and what can be done to stop it. C9orf72 harbors a hexanucleotide repeat, GGGGCC, in a non-coding region of the gene and a massive expansion of this repeat causes ALS, FTD, or both (FTD/ALS). Many questions lie ahead. What does this gene normally do? What is the consequence of an enormous GGGGCC repeat expansion on that gene’s function? Could that hexanucleotide repeat expansion have additional pathological actions unrelated to C9orf72 function? There has been tremendous progress on all fronts in the quest to define how C9orf72 mutations cause disease. Many new experimental models have been constructed and unleashed in powerful genetic screens. Studies in mouse and human patient samples, including iPS-derived neurons, have provided unprecedented insights into pathogenic mechanisms. Three major hypotheses have emerged and are still being hotly debated in the field. These include 1) loss of function owing to decrease in the abundance of C9orf72 protein and its ability to carryout its still unknown cellular role; 2) RNA toxicity from bidirectionally transcribed sense (GGGGCC) and antisense (GGCCCC) transcripts that accumulate in RNA foci and might sequester critical RNA-binding proteins; 3) proteotoxicity from dipeptide repeat proteins produced by an unconventional form of translation from the expanded nucleotide repeats. Here we review the evidence in favor and against each of these three hypotheses. We also suggest additional experiments and considerations that we propose will help clarify which mechanism(s) are most important for driving disease and therefore most critical for considering during the development of therapeutic interventions.

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“…GGGGCC repeats and some DPRs colocalise in the nucleolus, the site where rRNAs are processed and assembled 54. Nucleolar dysfunction has been reported in patients and several models (figure 2),54 55 although the specific mechanisms mediating this toxicity are unknown at this time.…”

Section: C9orf72 and Mechanisms Of Toxicitymentioning

confidence: 99%

Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum

Ji¹,

Zhang

Chen

et al. 2017

J Med Genet

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Recent genetic discoveries have dramatically changed our understanding of two major neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are common, devastating diseases of the brain. For decades, ALS and FTD were classified as movement and cognitive disorders, respectively, due to their distinct clinical phenotypes. The recent identification of chromosome 9 open reading frame 72 (C9orf72) as the major gene causative of familial forms of ALS and FTD uncovered a new reality of a continuous FTD/ALS spectrum. The finding that up to 50% of all patients present some degree of ALS and FTD phenotypes supports this ALS/FTD continuum. Now >100 genes are known to contribute to ALS/FTD, with a few major contributors that are reviewed below. The low penetrance of C9orf72 mutations, its contribution to sporadic cases, and its combination with other genes support an oligogenic model where two or more genes contribute to disease risk, onset, progression and phenotype: from 'pure' ALS or FTD to combined ALS/ FTD. These advances in the genetics of ALS/FTD will soon lead to a better mechanistic understanding of the pathobiology of the disease, which should result in the development of effective therapies in the near future.

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C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD

Cited by 267 publications

References 36 publications

Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

There has been an awakening: Emerging mechanisms of C9orf72 mutations in FTD/ALS

Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum

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