p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)

Maor-Nof, Maya; Shipony, Zohar; López-González, Rodrigo; Nakayama, Lisa; Zhang, Yong Jie; Couthouis, Julien; Blum, Jacob A.; Castruita, Patricia A.; Linares, Gabriel; Ruan, Kai; Ramaswami, Gokul; Simon, David; Nof, Aviv; Santana, Manuel; Han, Ke; Sinnott-Armstrong, Nasa; Bassik, Michael C.; Geschwind, Daniel H.; Tessier‐Lavigne, Marc; Attardi, Laura D.; Lloyd, Thomas E.; Ichida, Justin K.; Gao, Fen Biao; Greenleaf, William J.; Yokoyama, Jennifer S.; Petrucelli, Leonard; Gitler, Aaron D.

doi:10.1016/j.cell.2020.12.025

Cited by 113 publications

(116 citation statements)

References 124 publications

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“…In this context, the role played by the accumulation of cytotoxic aggregates appears to be crucial. In fact, these pathological features can be triggered by acutely expressing poly (GA) in primary neurons, and impaired synaptic transcriptome has been found also when overexpressing poly(PR) as well (Maor-Nof et al, 2021). The accumulation of such aberrant structures has indeed been associated with increased ER and oxidative stress (Zhang et al, 2014), which alter CREB activation (Seo et al, 2010;Pregi et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

Synaptic disruption and CREB‐regulated transcription are restored by K ⁺ channel blockers in ALS

et al. 2021

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which is still missing effective therapeutic strategies. Although manipulation of neuronal excitability has been tested in murine and human ALS models, it is still under debate whether neuronal activity might represent a valid target for efficient therapies. In this study, we exploited a combination of transcriptomics, proteomics, optogenetics and pharmacological approaches to investigate the activity-related pathological features of iPSC-derived C9orf72-mutant motoneurons (MN). We found that human ALS C9orf72 MN are characterized by accumulation of aberrant aggresomes, reduced expression of synaptic genes, loss of synaptic contacts and a dynamic "malactivation" of the transcription factor CREB. A similar phenotype was also found in TBK1-mutant MN and upon overexpression of poly(GA) aggregates in primary neurons, indicating a strong convergence of pathological phenotypes on synaptic dysregulation. Notably, these alterations, along with neuronal survival, could be rescued by treating ALS-related neurons with the K + channel blockers Apamin and XE991, which, respectively, target the SK and the Kv7 channels. Thus, our study shows that restoring the activitydependent transcriptional programme and synaptic composition exerts a neuroprotective effect on ALS disease progression.

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Section: Resultsmentioning

confidence: 99%

Synaptic disruption and CREB‐regulated transcription are restored by K ⁺ channel blockers in ALS

et al. 2021

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“…Specifically, the presence of an RRP induces PrLD LLPS, whereas RNA can promote LLPS of RRPs but not of PrLDs, underscoring the importance of arginine in forming protein : RNA condensates [66]. These findings may be of relevance in C9-ALS/FTD, where arginine-rich DPRs are particularly toxic [67][68][69][70][71][72][73][74]. Intriguingly, RRP : RNA condensates adopt an internal structure when one component is present in excess over the other, with the more abundant molecule residing on the surface of the condensate [66].…”

Section: Protein and Rna As Organizational Scaffoldsmentioning

confidence: 90%

Higher-order organization of biomolecular condensates

et al. 2021

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A guiding principle of biology is that biochemical reactions must be organized in space and time. One way this spatio-temporal organization is achieved is through liquid–liquid phase separation (LLPS), which generates biomolecular condensates. These condensates are dynamic and reactive, and often contain a complex mixture of proteins and nucleic acids. In this review, we discuss how underlying physical and chemical processes generate internal condensate architectures. We then outline the diverse condensate architectures that are observed in biological systems. Finally, we discuss how specific condensate organization is critical for specific biological functions.

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“…The significance of this effect remains unclear, however, as C9ORF72-ALS motor neurons and cells transfected with poly(GR) or poly(PR) DPRs show an expected increase in pATM, 53BP1 and phosphorylated p53 expression, corresponding with the observed DNA damage [58,62,73]. Importantly, p53 appears to play a key role in C9ORF72-ALS and DPRinduced toxicity as p53 knockout or knockdown has been shown to extend the lifespan of a mouse model expressing poly(PR), and protect against neurodegeneration in Drosophila models expressing the C9ORF72 repeat expansion [74]. Strikingly, p53 knockout also reduces DNA damage (γH2AX levels and comet tail measurements) in poly(PR) transduced cells and C9ORF72-ALS iPSC-derived motor neurons, indicating p53 action may be occurring upstream of DNA damage rather than downstream [74].…”

Section: Specific Als Subtypes and Dna Damage C9orf72mentioning

confidence: 95%

“…Importantly, p53 appears to play a key role in C9ORF72-ALS and DPRinduced toxicity as p53 knockout or knockdown has been shown to extend the lifespan of a mouse model expressing poly(PR), and protect against neurodegeneration in Drosophila models expressing the C9ORF72 repeat expansion [74]. Strikingly, p53 knockout also reduces DNA damage (γH2AX levels and comet tail measurements) in poly(PR) transduced cells and C9ORF72-ALS iPSC-derived motor neurons, indicating p53 action may be occurring upstream of DNA damage rather than downstream [74].…”

Section: Specific Als Subtypes and Dna Damage C9orf72mentioning

confidence: 99%

DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity

Kok

Palminha

Souza

et al. 2021

Cell. Mol. Life Sci.

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Increasing evidence supports the involvement of DNA damage in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Elevated levels of DNA damage are consistently observed in both sporadic and familial forms of ALS and may also play a role in Western Pacific ALS, which is thought to have an environmental cause. The cause of DNA damage in ALS remains unclear but likely differs between genetic subgroups. Repeat expansion in the C9ORF72 gene is the most common genetic cause of familial ALS and responsible for about 10% of sporadic cases. These genetic mutations are known to cause R-loops, thus increasing genomic instability and DNA damage, and generate dipeptide repeat proteins, which have been shown to lead to DNA damage and impairment of the DNA damage response. Similarly, several genes associated with ALS including TARDBP, FUS, NEK1, SQSTM1 and SETX are known to play a role in DNA repair and the DNA damage response, and thus may contribute to neuronal death via these pathways. Another consistent feature present in both sporadic and familial ALS is the ability of astrocytes to induce motor neuron death, although the factors causing this toxicity remain largely unknown. In this review, we summarise the evidence for DNA damage playing a causative or secondary role in the pathogenesis of ALS as well as discuss the possible mechanisms involved in different genetic subtypes with particular focus on the role of astrocytes initiating or perpetuating DNA damage in neurons.

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p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)

Cited by 113 publications

References 124 publications

Synaptic disruption and CREB‐regulated transcription are restored by K ⁺ channel blockers in ALS

Synaptic disruption and CREB‐regulated transcription are restored by K ⁺ channel blockers in ALS

Higher-order organization of biomolecular condensates

DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity

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p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)

Cited by 113 publications

References 124 publications

Synaptic disruption and CREB‐regulated transcription are restored by K + channel blockers in ALS

Synaptic disruption and CREB‐regulated transcription are restored by K + channel blockers in ALS

Higher-order organization of biomolecular condensates

DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity

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Synaptic disruption and CREB‐regulated transcription are restored by K ⁺ channel blockers in ALS

Synaptic disruption and CREB‐regulated transcription are restored by K ⁺ channel blockers in ALS