Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent integrated stress response in C9orf72 FTD/ALS

Parameswaran, Janani; Zhang, Nancy R.; Tilahun, Kedamawit; Pant, Devesh C; Chilukuri, Ganesh; Asress, Seneshaw; Banerjee, Anwesha; Davis, Emma; Schwartz, Samantha L.; Conn, Graeme L.; Bassell, Gary J.; Jiang, Jie

doi:10.1101/2022.06.06.495030

Cited by 7 publications

(9 citation statements)

References 78 publications

(129 reference statements)

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“…In addition, mice expressing ALSassociated mutant SOD1 [43,47] or ALS and FTD-associated FUS [48] also display activation of ISR and/or impairment of ongoing protein synthesis, including upregulation of Chop [49]. The ISR is also activated in neurons expressing expanded C9orf72 hexanucleotide repeats, and is similarly seen in the cortices of people who have died with C9orf72-linked ALS and FTD [50]. Together, these studies indicate that ISR activation, and Chop in particular, is involved broadly in disease, although it remains unclear whether these pathways may be amenable to therapeutic targeting in TDP-43-related disease.…”

Section: Discussionmentioning

confidence: 99%

Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS and FTD

et al. 2023

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TAR DNA binding protein 43 (TDP-43) pathology is a key feature of over 95% of amyotrophic lateral sclerosis (ALS) and nearly half of frontotemporal dementia (FTD) cases. The pathogenic mechanisms of TDP-43 dysfunction are poorly understood, however, activation of cell stress pathways may contribute to pathogenesis. We, therefore, sought to identify which cell stress components are critical for driving disease onset and neurodegeneration in ALS and FTD. We studied the rNLS8 transgenic mouse model, which expresses human TDP-43 with a genetically-ablated nuclear localisation sequence within neurons of the brain and spinal cord resulting in cytoplasmic TDP-43 pathology and progressive motor dysfunction. Amongst numerous cell stress-related biological pathways profiled using qPCR arrays, several critical integrated stress response (ISR) effectors, including CCAAT/enhancer-binding homologous protein (Chop/Ddit3) and activating transcription factor 4 (Atf4), were upregulated in the cortex of rNLS8 mice prior to disease onset. This was accompanied by early up-regulation of anti-apoptotic gene Bcl2 and diverse pro-apoptotic genes including BH3-interacting domain death agonist (Bid). However, pro-apoptotic signalling predominated after onset of motor phenotypes. Notably, pro-apoptotic cleaved caspase-3 protein was elevated in the cortex of rNLS8 mice at later disease stages, suggesting that downstream activation of apoptosis drives neurodegeneration following failure of early protective responses. Unexpectedly, suppression of Chop in the brain and spinal cord using antisense oligonucleotide-mediated silencing had no effect on overall TDP-43 pathology or disease phenotypes in rNLS8 mice. Cytoplasmic TDP-43 accumulation therefore causes very early activation of ISR and both anti- and pro-apoptotic signalling that switches to predominant pro-apoptotic activation later in disease. These findings suggest that precise temporal modulation of cell stress and death pathways may be beneficial to protect against neurodegeneration in ALS and FTD.

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Section: Discussionmentioning

confidence: 99%

Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS and FTD

et al. 2023

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“…Previous research show depletion of TDP-43 or ALS-linked mutant TDP-43 induces DNA damage and consequently p53-dependent apoptosis of motor neurons (42,43), while GADD45G acts as a stress sensor for p53-mediated apoptosis (44,45). Moreover, it is proposed that oxidative stress is a pathogenic mechanism in disease, in parallel with or downstream to ISR [4,35]. Our results reveal elevation of the oxidative stress-responsive gene Homx1 in the cortex of rNLS8 mice from the 2week time point (Fig 3C ), in line with the evidence from the motor cortex of ALS-linked mutant TDP-43 transgenic mice (6,46,47) and in the lumbar spinal cord of SOD1 G93A mice for ALS (48).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, mice expressing ALS-associated mutant SOD1 (29,32) or ALS/FTD-associated FUS (33) also display activation of ISR and/or impairment of ongoing protein synthesis, including upregulation of Chop (34). The ISR is also activated in neurons expressing expanded C9orf72 hexanucleotide repeats, and is similarly seen in the cortices of people who have died with C9orf72-linked ALS/FTD (35). Together, these studies indicate that the ISR, and Chop in particular, is involved broadly in disease, although it remains unclear whether these pathways may be amenable to therapeutic targeting in TDP-43-related disease.…”

Section: Discussionmentioning

confidence: 99%

Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS/FTD

Luan

Wright

Brown-Wright

et al. 2022

Preprint

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TAR DNA binding protein 43 (TDP-43) pathology is a key feature of over 95% of amyotrophic lateral sclerosis (ALS) and nearly half of frontotemporal dementia (FTD) cases. The pathogenic mechanisms of TDP-43 dysfunction are poorly understood, however activation of cell stress pathways may contribute to pathogenesis. We therefore sought to identify which cell stress components are critical for driving disease onset and neurodegeneration in ALS/FTD. We studied the rNLS8 transgenic mouse model, which expresses human TDP-43 with a genetically-ablated nuclear localisation sequence within neurons of the brain and spinal cord resulting in cytoplasmic TDP-43 pathology and progressive motor dysfunction. Amongst numerous cell stress-related biological pathways profiled using qPCR arrays, several critical ISR effectors, including CCAAT/enhancer-binding homologous protein (Chop/Ddit3) and activating transcription factor 4 (Atf4), were upregulated in the cortex of rNLS8 mice prior to disease onset. This was accompanied by early up-regulation of anti-apoptotic gene Bcl2 and diverse pro-apoptotic genes including BH3-interacting domain death agonist (Bid). However, pro-apoptotic signalling predominated after onset of motor phenotypes. Notably, pro-apoptotic caspase-3 protein was elevated in the cortex of rNLS8 mice at later disease stages, suggesting that downstream activation of apoptosis drives neurodegeneration following failure of early protective responses. Unexpectedly, suppression of Chop in the brain and spinal cord using antisense oligonucleotide-mediated silencing had no effect on overall TDP-43 pathology or disease phenotypes in rNLS8 mice. Cytoplasmic TDP-43 accumulation therefore causes very early activation of ISR and both anti- and pro-apoptotic signalling that switches to predominant pro-apoptotic activation later in disease. These findings suggest that precise temporal modulation of cell stress and death pathways may be beneficial to protect against neurodegeneration in ALS and FTD.

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“…PKR has been demonstrated to play a significant role in a variety of stresses including viral infection, tumor suppression, cell growth and proliferation, regulation of mitosis, as well as neurodegeneration and metabolic diseases 13–16 . In the context of viral infections, PKR has been shown to restrict the replication of both DNA and RNA viruses.…”

Section: Introductionmentioning

confidence: 99%

RNA recognition by PKR during DNA virus infection

Zhang,

Karijolich

2024

Journal of Medical Virology

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Protein kinase R (PKR) is a double‐stranded RNA (dsRNA) binding protein that plays a crucial role in innate immunity during viral infection and can restrict both DNA and RNA viruses. The potency of its antiviral function is further reflected by the large number of viral‐encoded PKR antagonists. However, much about the regulation of dsRNA accumulation and PKR activation during viral infection remains unknown. Since DNA viruses do not have an RNA genome or RNA replication intermediates like RNA viruses do, PKR‐mediated dsRNA detection in the context of DNA virus infection is particularly intriguing. Here, we review the current state of knowledge regarding the regulation of PKR activation and its antagonism during infection with DNA viruses.

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Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent integrated stress response in C9orf72 FTD/ALS

Cited by 7 publications

References 78 publications

Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS and FTD

Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS and FTD

Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS/FTD

RNA recognition by PKR during DNA virus infection

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