The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis

Cooper‐Knock, Johnathan; Kirby, Janine; Highley, J. Robin; Shaw, Pamela J.

doi:10.1007/s13311-015-0342-1

Cited by 48 publications

(40 citation statements)

References 129 publications

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“…These neuronal populations were chosen as they all exhibit neurodegeneration in C9ORF72 -ALS and are characteristic of both motor (motor neurons) and extra-motor (cerebellum and hippocampus) pathology [4]. Sequential sections of tissue from C9ORF72 -ALS cases, non- C9ORF72 ALS cases, and controls were examined for RNA foci in a blinded manner.…”

Section: Resultsmentioning

confidence: 99%

Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy

et al. 2015

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GGGGCC repeat expansions of C9ORF72 represent the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We and others have proposed that RNA transcribed from the repeat sequence is toxic via sequestration of RNA-binding factors. Both GGGGCC-repeat (sense) and CCCCGG-repeat (antisense) molecules are detectable by fluorescence in situ hybridisation as RNA foci, but their relative expression pattern within the CNS and contribution to disease has not been determined. Blinded examination of CNS biosamples from ALS patients with a repeat expansion of C9ORF72 showed that antisense foci are present at a significantly higher frequency in cerebellar Purkinje neurons and motor neurons, whereas sense foci are present at a significantly higher frequency in cerebellar granule neurons. Consistent with this, inclusions containing sense or antisense derived dipeptide repeat proteins were present at significantly higher frequency in cerebellar granule neurons or motor neurons, respectively. Immunohistochemistry and UV-crosslinking studies showed that sense and antisense RNA molecules share similar interactions with SRSF2, hnRNP K, hnRNP A1, ALYREF, and hnRNP H/F. Together these data suggest that, although sense and antisense RNA molecules might be expected to be equally toxic via their shared protein binding partners, distinct patterns of expression in various CNS neuronal populations could lead to relative differences in their contribution to the pathogenesis of neuronal injury. Moreover in motor neurons, which are the primary target of pathology in ALS, the presence of antisense foci (χ2, p < 0.00001) but not sense foci (χ2, p = 0.75) correlated with mislocalisation of TDP-43, which is the hallmark of ALS neurodegeneration. This has implications for translational approaches to C9ORF72 disease, and furthermore interacting RNA-processing factors and transcriptional activators responsible for antisense versus sense transcription might represent novel therapeutic targets.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1429-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy

et al. 2015

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“…The pathogenic mechanisms behind this repeat expansion have been reviewed elsewhere, but may include toxic gain-of-function, namely via RNA toxicity and DPR formation, or alternatively loss-of-function via C9ORF72 haploinsufficiency (reviewed in Cooper-Knock et al, 2015; Haeusler et al, 2016). With evidence for all three mechanisms in patients and a range of models, it is likely that all three mechanisms are at play.…”

Section: Loss Of Protein Homeostasis In Alsmentioning

confidence: 99%

Protein Homeostasis in Amyotrophic Lateral Sclerosis: Therapeutic Opportunities?

Webster

Smith

Shaw

et al. 2017

Front. Mol. Neurosci.

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Protein homeostasis (proteostasis), the correct balance between production and degradation of proteins, is essential for the health and survival of cells. Proteostasis requires an intricate network of protein quality control pathways (the proteostasis network) that work to prevent protein aggregation and maintain proteome health throughout the lifespan of the cell. Collapse of proteostasis has been implicated in the etiology of a number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), the most common adult onset motor neuron disorder. Here, we review the evidence linking dysfunctional proteostasis to the etiology of ALS and discuss how ALS-associated insults affect the proteostasis network. Finally, we discuss the potential therapeutic benefit of proteostasis network modulation in ALS.

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“…Compared to fALS patients with other mutations, bulbar onset was more common with C9orf72 mutation [39,41]. When compared to ALS subjects without the repeat expansion (82), those with the C9 mutation (9) had a significantly faster rate of motor progression as per the total ALS functional rating scale [37•].…”

Section: Demographics Of C9orf72 In Ftd and Alsmentioning

confidence: 99%

Cognitive Profile of C9orf72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Patel

Sampson

2015

Curr Neurol Neurosci Rep

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This review article focuses on the cognitive profile associated with the C9orf72 gene with GGGGCC (G4C2) hexanucleotide repeat expansions that is commonly found in both familial and sporadic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in order to aid clinicians in the screening process. In this growing clinical continuum between FTD and ALS, understanding and recognizing a neurocognitive profile is important for diagnosis. Key features of this profile include executive dysfunction with memory impairment and language deficits as the disease progresses. Behaviorally, patients are prone to disinhibition, apathy, and psychosis. With the discovery of this mutation, studies have begun to characterize the different phenotypes associated with this mutation in terms of epidemiology, clinical presentation, imaging, and pathology. Greater awareness and increased surveillance for this mutation will benefit patients and their families in terms of access to genetic counseling, research studies, and improved understanding of the disease process.

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The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis

Cited by 48 publications

References 129 publications

Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy

Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy

Protein Homeostasis in Amyotrophic Lateral Sclerosis: Therapeutic Opportunities?

Cognitive Profile of C9orf72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

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