The cerebellar degeneration in ataxia-telangiectasia: A case for genome instability

Shiloh, Yosef

doi:10.1016/j.dnarep.2020.102950

Cited by 40 publications

(37 citation statements)

References 268 publications

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“…The increased protein aggregation that occurs after a loss of ATM – including in A-T patient brains – has been recently attributed to an accumulation of DNA damage (Lee et al 2021). As an impaired response to DNA damage is believed to be the primary driving force of A-T phenotypes (Shiloh 2020), these findings have fueled the idea that a disruption of protein homeostasis may be an important disease mechanism in A-T. Our data provide further support for this, as they show that the widespread aggregation caused by a loss of ATM follows a predictable pattern that overlaps strikingly with the aggregation that is believed to underlie many neurodegenerative disorders. Importantly, our findings also provide a proof of principle that other genotoxic conditions – including chemotherapeutic topoisomerase poisons – can have a very similar impact.…”

Section: Discussionsupporting

confidence: 66%

Targeting DNA topoisomerases or checkpoint kinases results in an overload of chaperone systems, triggering aggregation of a metastable subproteome

Huiting

et al. 2021

Preprint

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A loss of the checkpoint kinase ATM leads to impairments in the DNA damage response, and in humans causes cerebellar neurodegeneration, and a high risk to cancer. A loss of ATM is also associated with increased protein aggregation. The relevance and characteristics of this aggregation are still incompletely understood. Moreover, it is unclear to what extent other genotoxic conditions can trigger protein aggregation as well. Here, we show that targeting ATM, but also ATR or DNA topoisomerases result in a similar, widespread aggregation of a metastable, disease-associated subfraction of the proteome. Aggregation-prone model substrates, including Huntingtin exon1 containing an expanded polyglutamine repeat, aggregate faster under these conditions. This increased aggregation results from an overload of chaperone systems, which lowers the cell-intrinsic threshold for proteins to aggregate. In line with this, we find that inhibition of the HSP70 chaperone system further exacerbates the increased protein aggregation. Moreover, we identify the molecular chaperone HSPB5 as a potent suppressor of it. Our findings reveal that various genotoxic conditions trigger widespread protein aggregation in a manner that is highly reminiscent of the aggregation occurring in situations of proteotoxic stress and in proteinopathies.

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Section: Discussionsupporting

confidence: 66%

Targeting DNA topoisomerases or checkpoint kinases results in an overload of chaperone systems, triggering aggregation of a metastable subproteome

Huiting

et al. 2021

Preprint

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“…In agreement with this, loss of kinase activity of the yeast ATM/ATR kinase Mec1-or its downstream signaling targets-also causes widespread protein aggregation and confers sensitivity to stresses challenging protein homeostasis (Corcoles-Saez et al 2018). Considering the notion that in A-T, it is-arguably-the absence of ATM's central role in the response to DNA damage which is responsible for the strong cerebellar degeneration observed (Shiloh 2020), this raises the question if genomic instability-induced loss of protein homeostasis could be an underlying pathogenic mechanism in this context.…”

Section: Genome Maintenance Defects Are Causally Linked To a Loss Ofmentioning

confidence: 99%

Locked in a vicious cycle: the connection between genomic instability and a loss of protein homeostasis

Huiting

Bergink

2020

GENOME INSTAB. DIS.

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Cardiomyopathies, neuropathies, cancer and accelerated ageing are unequivocally distinct diseases, yet they also show overlapping pathological hallmarks, including a gradual loss of genomic integrity and proteotoxic stress. Recent lines of evidence suggest that this overlap could be the result of remarkably interconnected molecular cascades between nuclear genomic instability and a loss of protein homeostasis. In this review, we discuss these complex connections, as well as their possible impact on disease. We focus in particular on the inherent ability of a wide range of genomic alterations to challenge protein homeostasis. In doing so, we provide evidence suggesting that a loss of protein homeostasis could be a far more prevalent consequence of genomic instability than generally believed. In certain cases, such as aneuploidy, a loss of protein homeostasis appears to be a crucial mechanism for pathology, which indicates that enhancing protein quality control systems could be a promising therapeutic strategy in diseases associated with genomic instability.

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“…Null mutations in the Atm gene that cause the loss of functional ATM, a 370 kDa protein, results in severe characteristic cerebral ataxia and dilated blood vessels present in the conjunctivae of the eyes, also known as telangiectasia [6]. Moreover, nonfunctional ATM has been associated with an increased risk for cancer, radiation sensitivity, endocrine disruption, progressive neurodegeneration, premature ageing, and chromosomal instability (most recently reviewed by Shiloh [7]). The degree of disease severity is dependent on the type of mutation in the Atm gene (single or bi-allelic) and heterozygous patients, which make up as much as 1.4-2% of the general population, also exhibit a high incidence of ischaemic heart disease and insulin resistance [8,9].…”

Section: Introductionmentioning

confidence: 99%

Ataxia Telangiectasia Mutated Protein Kinase: A Potential Master Puppeteer of Oxidative Stress‐Induced Metabolic Recycling

Blignaut

Harries

Lochner

et al. 2021

Oxidative Medicine and Cellular Longevity

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Ataxia Telangiectasia Mutated protein kinase (ATM) has recently come to the fore as a regulatory protein fulfilling many roles in the fine balancing act of metabolic homeostasis. Best known for its role as a transducer of DNA damage repair, the activity of ATM in the cytosol is enjoying increasing attention, where it plays a central role in general cellular recycling (macroautophagy) as well as the targeted clearance (selective autophagy) of damaged mitochondria and peroxisomes in response to oxidative stress, independently of the DNA damage response. The importance of ATM activation by oxidative stress has also recently been highlighted in the clearance of protein aggregates, where the expression of a functional ATM construct that cannot be activated by oxidative stress resulted in widespread accumulation of protein aggregates. This review will discuss the role of ATM in general autophagy, mitophagy, and pexophagy as well as aggrephagy and crosstalk between oxidative stress as an activator of ATM and its potential role as a master regulator of these processes.

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The cerebellar degeneration in ataxia-telangiectasia: A case for genome instability

Cited by 40 publications

References 268 publications

Targeting DNA topoisomerases or checkpoint kinases results in an overload of chaperone systems, triggering aggregation of a metastable subproteome

Targeting DNA topoisomerases or checkpoint kinases results in an overload of chaperone systems, triggering aggregation of a metastable subproteome

Locked in a vicious cycle: the connection between genomic instability and a loss of protein homeostasis

Ataxia Telangiectasia Mutated Protein Kinase: A Potential Master Puppeteer of Oxidative Stress‐Induced Metabolic Recycling

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