Disease Mechanisms of<i>C9ORF72</i>Repeat Expansions

Gendron, Tania F.; Petrucelli, Leonard

doi:10.1101/cshperspect.a024224

Cited by 80 publications

(60 citation statements)

References 132 publications

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“…UPS impairment has also been linked to C9orf72 mutations, the most common genetic cause of ALS/FTD (Edbauer and Haass, 2016; Freibaum and Taylor, 2017; Gendron and Petrucelli, 2017; Lin et al, 2017). A massive expansion of a GGGGCC (G 4 C 2 ) repeat in a non-coding region of the C9orf72 gene to up to several thousand copies is found in 10–50% of familial ALS/FTD cases and in 5–7% of patients with sporadic disease (DeJesus-Hernandez et al, 2011; Majounie et al, 2012; Renton et al, 2011; van der Zee et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment

Guo

Lehmer

Martínez-Sánchez

et al. 2018

Cell

340

317

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Summary Protein aggregation and dysfunction of the ubiquitin-proteasome system are hallmarks of many neurodegenerative diseases. Here we address the elusive link between these phenomena employing cryo-electron tomography to dissect the molecular architecture of protein aggregates within intact neurons at high resolution. We focus on the poly-Gly-Ala (GA) aggregates resulting from aberrant translation of an expanded GGGGCC repeat in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. We find that poly-GA aggregates consist of densely packed twisted ribbons that recruit numerous 26S proteasome complexes, while other macromolecules are largely excluded. Proximity to poly-GA ribbons stabilizes a transient substrate-processing conformation of the 26S proteasome, suggesting stalled degradation. Thus, poly-GA aggregates may compromise neuronal proteostasis by driving the accumulation and functional impairment of a large fraction of cellular proteasomes.

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Section: Introductionmentioning

confidence: 99%

In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment

Guo

Lehmer

Martínez-Sánchez

et al. 2018

Cell

340

317

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“…In the 6 years since a GGGGCC (or G4C2) hexanucleotide expansion in the C9ORF72 gene was discovered to cause familial ALS and FTD (112), our understanding of the ALS/FTD disease spectrum has advanced tremendously (27,42,48). The “C9 story” is one of rapid discoveries and unexpected biological convergences.…”

Section: Introductionmentioning

confidence: 99%

“…Though initial studies revealed modest reduction in expression of the C9ORF72 gene product (a protein of still uncertain function), it now seems clear that a partial loss of gene function, or haploinsufficiency, is not a major component of disease pathogenesis. Instead, compelling cases have been made both for RNA toxicity (the formation of RNA foci, sequestration of critical RNA-binding proteins and aberrant splicing) and proteotoxicity (RAN translation from both the sense and antisense transcripts, generating five distinct dipeptide proteins that vary in toxicity and propensity to aggregate) (14,34,35,42,48,80). Very likely, both pathways contribute to disease though many questions remain unanswered.…”

Section: Introductionmentioning

confidence: 99%

Repeat expansion diseases

Paulson

2018

Handbook of Clinical Neurology

324

286

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More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome. Expanded trinucleotide repeat diseases were discovered first and remain the most frequent. More recently tetra-, penta-, hexa-, and even dodeca-nucleotide repeat expansions have been identified as the cause of human disease, including some of the most common genetic disorders seen by neurologists. Repeat expansion diseases include both causes of myotonic dystrophy (DM1 and DM2), the most common genetic cause of amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72), Huntington disease, and eight other polyglutamine disorders, including the most common forms of dominantly inherited ataxia, the most common recessive ataxia (Friedreich ataxia), and the most common heritable mental retardation (fragile X syndrome). Here I review distinctive features of this group of diseases that stem from the unusual, dynamic nature of the underlying mutations. These features include marked clinical heterogeneity and the phenomenon of clinical anticipation. I then discuss the diverse molecular mechanisms driving disease pathogenesis, which vary depending on the repeat sequence, size, and location within the disease gene, and whether the repeat is translated into protein. I conclude with a brief clinical and genetic description of individual repeat expansion diseases that are most relevant to neurologists.

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“…We focus on the human pathological research because it is the literature we know best and because outstanding reviews of the model-based literature have been provided by leaders in the field [4, 38, 45, 48, 53, 168]. We present the literature from a systems neuroanatomical point of view, thinking critically about the brain regions examined and their relationship to the clinical syndromes under study.…”

Section: Introductionmentioning

confidence: 99%

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

et al. 2018

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What are the most important and treatable pathogenic mechanisms in C9orf72-FTD/ALS? Model-based efforts to address this question are forging ahead at a blistering pace, often with conflicting results. But what does the human neuropathological literature reveal? Here, we provide a critical review of the human studies to date, seeking to highlight key gaps or uncertainties in our knowledge. First, we engage the C9orf72-specific mechanisms, including C9orf72 haploinsufficiency, repeat RNA foci, and dipeptide repeat protein inclusions. We then turn to some of the most prominent C9orf72-associated features, such as TDP-43 loss-of-function, TDP-43 aggregation, and nuclear transport defects. Finally, we review potential disease-modifying epigenetic and genetic factors and the natural history of the disease across the lifespan. Throughout, we emphasize the importance of anatomical precision when studying how candidate mechanisms relate to neuronal, regional, and behavioral findings. We further highlight methodological approaches that may help address lingering knowledge gaps and uncertainties, as well as other logical next steps for the field. We conclude that anatomically oriented human neuropathological studies have a critical role to play in guiding this fast-moving field toward effective new therapies.

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Disease Mechanisms ofC9ORF72Repeat Expansions

Cited by 80 publications

References 132 publications

In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment

In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment

Repeat expansion diseases

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

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