RNA-mediated toxicity in C9orf72 ALS and FTD

McEachin, Zachary T.; Parameswaran, Janani; Raj, Nisha; Bassell, Gary J.; Jiang, Jie

doi:10.1016/j.nbd.2020.105055

Cited by 35 publications

(34 citation statements)

References 119 publications

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“…Conversely to sense RNA, we did not detect in vitro interaction between antisense RNA and SFPQ by RNA pull-down assay. This could be the consequence of secondary structures formed by sense and antisense RNA, which have been proposed to enable their interaction with various RNA binding proteins ( McEachin et al, 2020 ; Vatovec et al, 2014 ). Sense RNA forms mostly G quadruplexes and hairpins, whereas antisense RNA forms i-motifs along with C-rich hairpins ( Božič et al, 2020 ; Haeusler et al, 2014 ; Kovanda et al, 2016 ; Šket et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

SFPQ regulates the accumulation of RNA foci and dipeptide repeat proteins from the expanded repeat mutation in C9orf72

Malnar

Rogelj

2021

Journal of Cell Science

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The expanded GGGGCC repeat mutation in the C9orf72 gene is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion is transcribed to sense and antisense RNA, which form RNA foci and bind cellular proteins. This mechanism of action is considered cytotoxic. Translation of the expanded RNA transcripts also leads to the accumulation of toxic dipeptide repeat proteins (DPRs). The RNA-binding protein SFPQ, which is being increasingly associated with ALS/FTD pathology, binds to sense RNA foci. Here, we show that SFPQ plays an important role in the C9orf72 mutation. Overexpression of SFPQ resulted in higher numbers of both sense and antisense RNA foci and DPRs in transfected HEK cells. Conversely, reduced SPFQ levels resulted in lower numbers of RNA foci and DPRs in both transfected HEK cells and C9orf72 mutation-positive patient-derived fibroblasts and lymphoblasts. Therefore, we have revealed a role of SFPQ in regulating the C9orf72 mutation that has implications for understanding and developing novel therapeutic targets for ALS and FTD.

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Section: Discussionmentioning

confidence: 99%

SFPQ regulates the accumulation of RNA foci and dipeptide repeat proteins from the expanded repeat mutation in C9orf72

Malnar

Rogelj

2021

Journal of Cell Science

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“…Importantly, there is a differential distribution regarding the RNA foci formed by sense and anti-sense depending on the brain region, with sense RNA foci being more prevalent throughout the brain of patients (DeJesus-Hernandez et al, 2017), and anti-sense prevalent in Purkinje cells in the cerebellum and in lower motor neurons in the spinal cord and bulb (Cooper-Knock et al, 2015). A lack of correlation is reported between foci distribution and pathological signs of degeneration as they can be detected in both affected and unaffected brain regions (McEachin et al, 2020). Of note, a greater extent of anti-sense RNA foci present in the frontal cortex was statistically associated to a later onset of disease, especially for FTD cases, thus supporting the notion that the formation of such structures is rather neuroprotective (DeJesus-Hernandez et al, 2017).…”

Section: Gain-of-function: Rna Foci and Dpr Toxicitymentioning

confidence: 99%

“…RNA foci are able to sequester RNA-binding proteins (RBPs), leading to defects in the processing of RNA Todd & Petrucelli, 2018). Of note, RNA foci are primarily reported in the nucleus, but have also been found in the cytosol, in the edge of the nuclear membrane (McEachin et al, 2020) and also in neurites of C9ALS/FTD patient neurons derived from induced pluripotent stem cells (iPSCs) (Burguete et al, 2015). Importantly, there is a differential distribution regarding the RNA foci formed by sense and anti-sense depending on the brain region, with sense RNA foci being more prevalent throughout the brain of patients (DeJesus-Hernandez et al, 2017), and anti-sense prevalent in Purkinje cells in the cerebellum and in lower motor neurons in the spinal cord and bulb (Cooper-Knock et al, 2015).…”

Section: Gain-of-function: Rna Foci and Dpr Toxicitymentioning

confidence: 99%

Proteostasis deregulation as a driver of C9ORF72 pathogenesis

Torres

Cabral‐Miranda²,

Gonzalez-Teuber

et al. 2021

Journal of Neurochemistry

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative disorders that are characterized by motor and behavioral impairment, respectively. Importantly, ALS and FTD are clinically, pathologically, and genetically overlapped, forming part of a spectrum of diseases (Burrell et al., 2016). ALS is a neurodegenerative disorder that affects both upper and lower motor neurons

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“…Repeat-containing transcripts of the mutated C9orf72 gene can form RNA foci enriched with RNA-binding proteins in induced pluripotent stem cell (iPSC)-derived neurons from ALS and FTD patients, as well as in motor neurons of C9orf72-ALS patients [ 37 , 38 , 39 , 40 ]. Even though conflicting evidence remains about the mechanisms of toxicity of C9orf72 mutations [ 19 , 36 , 41 ], RNA foci are believed to sequestrate bound RNA-binding proteins and result in toxicity [ 42 ]. Dipeptide repeat (DPR), glycine-alanine (GA), glycine-arginine (GR), proline-arginine (PR), proline-alanine (PA), and glycine-proline (GP) are generated through repeat-associated non-ATG translation from hexanucleotide repeat expansion-containing transcripts [ 43 , 44 , 45 , 46 ].…”

Section: Rna-binding Proteins and Alsmentioning

confidence: 99%

RNA-Binding Proteins and the Complex Pathophysiology of ALS

Kim

Lee

2021

IJMS

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Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have identified disease-causing mutations and accelerated the unveiling of complex molecular pathogenic mechanisms, which may be important for understanding the disease and developing therapeutic strategies. Many disease-related genes encode RNA-binding proteins, and most of the disease-causing RNA or proteins encoded by these genes form aggregates and disrupt cellular function related to RNA metabolism. Disease-related RNA or proteins interact or sequester other RNA-binding proteins. Eventually, many disease-causing mutations lead to the dysregulation of nucleocytoplasmic shuttling, the dysfunction of stress granules, and the altered dynamic function of the nucleolus as well as other membrane-less organelles. As RNA-binding proteins are usually components of several RNA-binding protein complexes that have other roles, the dysregulation of RNA-binding proteins tends to cause diverse forms of cellular dysfunction. Therefore, understanding the role of RNA-binding proteins will help elucidate the complex pathophysiology of ALS. Here, we summarize the current knowledge regarding the function of disease-associated RNA-binding proteins and their role in the dysfunction of membrane-less organelles.

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RNA-mediated toxicity in C9orf72 ALS and FTD

Cited by 35 publications

References 119 publications

SFPQ regulates the accumulation of RNA foci and dipeptide repeat proteins from the expanded repeat mutation in C9orf72

SFPQ regulates the accumulation of RNA foci and dipeptide repeat proteins from the expanded repeat mutation in C9orf72

Proteostasis deregulation as a driver of C9ORF72 pathogenesis

RNA-Binding Proteins and the Complex Pathophysiology of ALS

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