C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation

Cheng, Weiwei; Wang, Shaopeng; Mestre, Alexander A.; Fu, Cheng; Makarem, Andres; Xian, Fengfan; Hayes, Lindsey R.; López-González, Rodrigo; Drenner, Kevin; Jiang, Jie; Cleveland, Don W.; Sun, Shuying

doi:10.1038/s41467-017-02495-z

Cited by 178 publications

(238 citation statements)

References 75 publications

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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%

“…The ISR decreases canonical translation while levels of p-eif2a, PERK, and ATF4 are increased. Together, this suggests that the combination of increased age-dependent stimulation of the ISR and slow DPR turnover rates could exacerbate a positive feedback loop for non-AUG-dependent DPR translation, which may lead to rapidly accumulating DPR levels that accelerate disease (Cheng et al, 2018). 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.…”

Section: Discussionsupporting

confidence: 90%

“…Additionally, in mice, trazodone and 1,3 DBM prevented the disease-linked pathology and rescued memory deficits in prion-diseased and tauopathy FTD mice (Halliday et al, 2017). These results confirmed previous findings that showed the use of PERK inhibitors may reduce DPR levels in C9orf72 NRE models (Cheng et al, 2018). Of the compounds we tested, we identified that a PERK inhibitor (GSK2606414), an eIF4E phosphorylation inhibitor (cercosporamide), trazodone, and 1,3 DBM cause a significant reduction in DPR levels relative to control when challenged with the stressors NaArs or TM (Fig 6A).…”

Section: Repetitive Neuronal Depolarization Increases C9orf72 Nre Nonsupporting

confidence: 88%

“…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: 99%

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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: Discussionsupporting

confidence: 90%

Section: Repetitive Neuronal Depolarization Increases C9orf72 Nre Nonsupporting

confidence: 88%

Section: Repetitive Neuronal Depolarization Increases C9orf72 Nre Nonmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

See 3 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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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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A chemogenomic approach is required for effective treatment of amyotrophic lateral sclerosis

Pampalakis

Angelis

Zingkou

et al. 2022

Clinical & Translational Med

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ALS is a fatal untreatable disease involving degeneration of motor neurons. Μultiple causative genes encoding proteins with versatile functions have been identified indicating that diverse biological pathways lead to ALS. Chemical entities still represent a promising choice to delay ALS progression, attenuate symptoms and/or increase life expectancy, but also gene‐based and stem cell‐based therapies are in the process of development, and some are tested in clinical trials. Various compounds proved effective in transgenic models overexpressing distinct ALS causative genes unfortunately though, they showed no efficacy in clinical trials. Notably, while animal models provide a uniform genetic background for preclinical testing, ALS patients are not stratified, and the distinct genetic forms of ALS are treated as one group, which could explain the observed discrepancies between treating genetically homogeneous mice and quite heterogeneous patient cohorts. We suggest that chemical entity‐genotype correlation should be exploited to guide patient stratification for pharmacotherapy, that is administered drugs should be selected based on the ALS genetic background.

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C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation

Cited by 178 publications

References 75 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

Staufen Impairs Autophagy in Neurodegeneration

A chemogenomic approach is required for effective treatment of amyotrophic lateral sclerosis

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