RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response

Green, Katelyn M.; Glineburg, M. Rebecca; Kearse, Michael G.; Flores, Brittany; Linsalata, Alexander E.; Fedak, Stephen J.; Goldstrohm, Aaron C.; Barmada, Sami J.; Todd, Peter K.

doi:10.1038/s41467-017-02200-0

Cited by 189 publications

(370 citation statements)

References 72 publications

(139 reference statements)

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“…Therefore, this work provides early findings for new therapeutic avenues to ameliorate toxic polypeptide production caused by the non-AUGdependent translation of NREs, which is a proposed pathogenic mechanism identified for a number of neurological or neuromuscular disorders. Consistent with recent findings (Green et al, 2017;Cheng et al, 2018;Sonobe et al, 2018), our results indicate that stress-induced dysregulation of the ISR can lead to an increase in C9orf72 NRE DPR production, which we show have slow turnover rates. The ISR decreases canonical translation while levels of p-eif2a, PERK, and ATF4 are increased.…”

Section: Discussionsupporting

confidence: 93%

“…To accomplish this with appreciable DPR levels translated in the absence of an AUG (Green et al, 2017), we transiently transfected each of the six C9-DPR reporter constructs into HEK293T cells, then performed filter-trap binding assays probing for the c-terminus HA affinity tag of the DPR reporter or directly detecting the DPRs using DPR-specific antibodies. To accomplish this with appreciable DPR levels translated in the absence of an AUG (Green et al, 2017), we transiently transfected each of the six C9-DPR reporter constructs into HEK293T cells, then performed filter-trap binding assays probing for the c-terminus HA affinity tag of the DPR reporter or directly detecting the DPRs using DPR-specific antibodies.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, recent work demonstrated that altered levels or modification to ISR-related proteins, such as phosphorylation of PERK or eif2a, leads to altered DPR levels (Green et al, 2017;Cheng et al, 2018). We identified that various cellular stress events converge on activation of the ISR and result in an increase in non-AUG-dependent translation of DPRs.…”

Section: Repetitive Neuronal Depolarization Increases C9orf72 Nre Nonmentioning

confidence: 87%

“…Age-dependent hyperexcitability or hypoexcitability and increased vulnerability to excitotoxicity in neurons have been reported in C9orf72 NRE models, including patient-derived motor neurons (Donnelly et al, 2013;Sareen et al, 2013;Wainger et al, 2014;Devlin et al, 2015;Shi et al, 2018) and patient tissue (Wainger & Cudkowicz, 2015). P-eif2a-dependent translational regulation is a key response element to cellular stress that has been shown to increase non-canonical translation of mRNAs (Chesnokova et al, 2017) and is implicated to have a role in C9orf72 NRE-linked RAN translation (Green et al, 2017;Cheng et al, 2018). One potential outcome from these events is the dynamic translational regulation of phosphorylated a-subunit of eukaryotic translation initiation factor 2 (p-eif2a).…”

Section: Introductionmentioning

confidence: 98%

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Repeat‐associated non‐ AUG translation in C9orf72‐ ALS / FTD is driven by neuronal excitation and stress

et al. 2019

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Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat‐associated non‐AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of RAN translation are not well understood. Here we analyzed whether different cellular stressors promote RAN translation of dipeptide repeats (DPRs) associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or optogenetically increasing neuronal activity by repetitive trains of depolarization induced DPR formation in primary cortical neurons and patient derived spinal motor neurons. Increases in the integrated stress response (ISR) were concomitant with increased RAN translation of DPRs, both in neurons and different cell lines. Targeting phosphorylated‐PERK and the phosphorylated‐eif2α complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR‐dependent disease pathogenesis in NRE‐linked diseases.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Repetitive Neuronal Depolarization Increases C9orf72 Nre Nonmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Repeat‐associated non‐ AUG translation in C9orf72‐ ALS / FTD is driven by neuronal excitation and stress

et al. 2019

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“…For example, it is unclear whether the RNA substrate for translation is the unspliced pre-mRNA, mature spliced mRNA, or spliced out intron RNA (in cases where the repeat is intronic). Recent work suggests that RAN translation does require some canonical translational components, such as the 7’methylguaninie cap at the 5’ end of the RNA (Kearse, Green et al 2016, Green, Glineburg et al 2017). Nevertheless, the data strongly suggest that RAN translation plays a significant but previously unappreciated role in the pathogenesis of repeat expansion disorders.…”

Section: Introductionmentioning

confidence: 99%

Models and mechanisms of repeat expansion disorders: a worm’s eye view

Rudich

Lamitina

2018

J Genet

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The inappropriate genetic expansion of various repetitive DNA sequences underlies over 20 distinct inherited diseases. The genetic context of these repeats in exons, introns and untranslated regions has played a major role in thinking about the mechanisms by which various repeat expansions might cause disease. Repeat expansions in exons are thought to give rise to expanded toxic protein repeats (i.e. polyQ). Repeat expansions in introns and UTRs (i.e. FXTAS) are thought to produce aberrant repeat-bearing RNAs that interact with and sequester a wide variety of essential proteins, resulting in cellular toxicity. However, a new phenomenon termed 'repeat-associated nonAUG dependent (RAN) translation' paints a new and unifying picture of how distinct repeat expansion-bearing RNAs might act as substrates for this noncanonical form of translation, leading to the production of a wide range of repeat sequence-specific-encoded toxic proteins. Here, we review how the model system has been utilized to model many repeat disorders and discuss how RAN translation could be a previously unappreciated contributor to the toxicity associated with these different models.

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Staufen Impairs Autophagy in Neurodegeneration

Paul

Dansithong

Gandelman

et al. 2022

Annals of Neurology

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Objective The mechanistic target of rapamycin (mTOR) kinase is one of the master coordinators of cellular stress responses, regulating metabolism, autophagy, and apoptosis. We recently reported that staufen1 (STAU1), a stress granule (SG) protein, was overabundant in fibroblast cell lines from patients with spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis, frontotemporal degeneration, Huntington's, Alzheimer's, and Parkinson's diseases as well as animal models, and patient tissues. STAU1 overabundance is associated with mTOR hyperactivation and links SG formation with autophagy. Our objective was to determine the mechanism of mTOR regulation by STAU1. Methods We determined STAU1 abundance with disease‐ and chemical‐induced cellular stressors in patient cells and animal models. We also used RNA‐binding assays to contextualize STAU1 interaction with MTOR mRNA. Results STAU1 and mTOR were overabundant in bacterial artificial chromosome (BAC)‐C9ORF72, ATXN2Q127, and Thy1‐TDP‐43 transgenic mouse models. Reducing STAU1 levels in these mice normalized mTOR levels and activity and autophagy‐related marker proteins. We also saw increased STAU1 levels in HEK293 cells transfected to express C9ORF72‐relevant dipeptide repeats (DPRs). Conversely, DPR accumulations were not observed in cells treated by STAU1 RNA interference (RNAi). Overexpression of STAU1 in HEK293 cells increased mTOR levels through direct MTOR mRNA interaction, activating downstream targets and impairing autophagic flux. Targeting mTOR by rapamycin or RNAi normalized STAU1 abundance in an SCA2 cellular model. Interpretation STAU1 interaction with mTOR drives its hyperactivation and inhibits autophagic flux in multiple models of neurodegeneration. Staufen, therefore, constitutes a novel target to modulate mTOR activity and autophagy, and for the treatment of neurodegenerative diseases. ANN NEUROL 2023;93:398–416

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RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response

Cited by 189 publications

References 72 publications

Repeat‐associated non‐ AUG translation in C9orf72‐ ALS / FTD is driven by neuronal excitation and stress

Repeat‐associated non‐ AUG translation in C9orf72‐ ALS / FTD is driven by neuronal excitation and stress

Models and mechanisms of repeat expansion disorders: a worm’s eye view

Staufen Impairs Autophagy in Neurodegeneration

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