Unconventional features of C9ORF72 expanded repeat in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Vatovec, Sabina; Kovanda, Anja; Rogelj, Boris

doi:10.1016/j.neurobiolaging.2014.04.015

Cited by 44 publications

(57 citation statements)

References 129 publications

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“…This While the repeat length remains variable between affected individuals, there may be length variability within the same individual in different tissue samples (somatic variation). The significance of repeat number remains unclear [11]. In those with a pathological expansion of 30 or more G 4 C 2 repeats [2], there is almost full penetrance by the age of 80, 50 % penetrance by age 58, and rare penetrance before age 35 [12].…”

Section: Diagnosis and Geneticsmentioning

confidence: 99%

“…The second proposes repeat-associated RNA toxicity. The third proposes repeat-associated translation of pathogenic repeats leading to dipeptide repeat proteins (RAN translation) [11,50]. There is evidence of cytoplasmic aggregates of the RNA-binding protein, TAR DNA-binding protein (TDP-43) in both C9ALS and C9FTD [11].…”

Section: Neuropathologymentioning

confidence: 99%

“…The third proposes repeat-associated translation of pathogenic repeats leading to dipeptide repeat proteins (RAN translation) [11,50]. There is evidence of cytoplasmic aggregates of the RNA-binding protein, TAR DNA-binding protein (TDP-43) in both C9ALS and C9FTD [11]. The G 4 C 2 repeat expansions result in TDP-43 aggregation in disease relevant regions of the brain, defining C9orf72 as a TDP-43 proteinopathy.…”

Section: Neuropathologymentioning

confidence: 99%

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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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Section: Diagnosis and Geneticsmentioning

confidence: 99%

Section: Neuropathologymentioning

confidence: 99%

Section: Neuropathologymentioning

confidence: 99%

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Cognitive Profile of C9orf72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Patel

Sampson

2015

Curr Neurol Neurosci Rep

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“…Several studies have employed biochemical techniques to identify binding partners of the expanded sense repeat in vitro using differing methods and sources of protein, reviewed in [44]. Sequestration of some of these proteins into sense RNA foci has been assessed in patient-derived cells and tissue (Table 2).…”

Section: Gain Of Function: Repeat Rnamentioning

confidence: 99%

C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia

Mizielinska

Isaacs

2014

Current Opinion in Neurology

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Purpose of reviewThe molecular mechanisms that underlie chromosome 9 open reading frame 72 (C9orf72)-associated amyotrophic lateral sclerosis and frontotemporal dementia are rapidly emerging. Two potential disease mechanisms have been postulated – gain or loss of function. We provide an overview of recent advances that support or oppose gain-of-function and loss-of-function mechanisms.Recent findingsSince the discovery that a noncoding repeat expansion in C9orf72 was responsible for chromosome 9-linked amyotrophic lateral sclerosis and frontotemporal dementia in 2011, a plethora of studies have investigated clinical, pathological and mechanistic aspects of the disease. Loss of function is supported by reduced levels of C9orf72 in patient brain and functional work, revealing a role of the C9orf72 protein in endocytic and autophagic pathways and motor function. Gain of function is supported by the presence in patient brain of both repeat RNA and protein aggregates. Repeat RNA aggregates termed RNA foci, a hallmark of noncoding repeat expansion diseases, have been shown to sequester proteins involved in RNA splicing, editing, nuclear export and nucleolar function. Repeat-associated non-ATG dependent translation gives rise to toxic dipeptide repeat proteins that form inclusions in patient tissue. Antisense oligonucleotides targeting C9orf72 have shown promise for combating gain-of-function toxicity.SummaryRapid progress is being made towards understanding this common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Overall, the weight of data currently sits in favour of gain of function as the most important disease mechanism, which has important implications for the development of effective and targeted therapies.

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“…In addition, these neurons exhibit aberrant gene expression of some neuronal and secreted transcripts [58,60]. To date, a number of GGGGCC interactors have been identified via biochemical and immunohistochemical means [130]. For example, ADARB2, an RNA-editing enzyme, has been shown to co-localize and biochemically interact with the GGGGCC repeat, and its depletion has been shown to enhance glutamate toxicity in control iPS neurons.…”

Section: Mutations Of Rna Processing Proteins and Toxic Rnas In Alsmentioning

confidence: 99%

Aberrant Rna Homeostasis in Amyotrophic Lateral Sclerosis: Potential for New Therapeutic targets?

Donnelly

Grima

Sattler

2014

Neurodegener. Dis. Manag.

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Summary Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration. The disease pathogenesis is multifaceted in that multiple cellular and molecular pathways have been identified as contributors to the disease progression. Consequently, numerous therapeutic targets have been pursued for clinical development, unfortunately with little success. The recent discovery of mutations in RNA modulating genes such as TARDBP/TDP-43, FUS/TLS or C9ORF72 changed our understanding of neurodegenerative mechanisms in ALS and introduced the role of dysfunctional RNA processing as a significant contributor to disease pathogenesis. This article discusses the latest findings on such RNA toxicity pathways in ALS and potential novel therapeutic approaches.

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Unconventional features of C9ORF72 expanded repeat in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Cited by 44 publications

References 129 publications

Cognitive Profile of C9orf72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Cognitive Profile of C9orf72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia

Aberrant Rna Homeostasis in Amyotrophic Lateral Sclerosis: Potential for New Therapeutic targets?

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