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

Huiting, Wouter; Bergink, Steven

doi:10.1007/s42764-020-00027-6

Cited by 13 publications

(8 citation statements)

References 247 publications

(268 reference statements)

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“…One of the factors underlying the AD-like phenotypes observed in GBM patients may be the genotoxic effects of radiotherapy and chemotherapy 22,23 . Indeed, studies have shown an association between DNA damage and a loss of protein homeostasis [24][25][26][27] . Remarkably, the proteins that aggregate after genotoxic stress overlap with proteins that aggregate in the background of neurodegenerative disease including AD 27 .…”

Section: Discussionmentioning

confidence: 99%

Glioblastoma is associated with extensive accelerated brain ageing

Ainslie

Klaver

Voshart

et al. 2022

Preprint

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Progressive neurocognitive dysfunction is the leading cause of a reduced quality of life in patients with primary brain tumours. Understanding the mechanisms underlying cognitive impairments that occur in response to a brain tumour and its treatment is essential to improve patients′ quality of life. Here, we show that normal-appearing non-tumour brain regions of patients with glioblastoma display hallmarks of accelerated ageing and share multiple features with Alzheimer′s disease patients. Integrated transcriptomic and tissue analysis shows that normal-appearing brain tissue from glioblastoma patients has a significant overlap with brain tissue from Alzheimer′s disease patients, revealing shared mitochondrial and neuronal dysfunction, and proteostasis deregulation. Overall, the brain of glioblastoma patients undergoes Alzheimer′s disease-like accelerated ageing, providing novel or repurposed therapeutic targets for managing brain cancer-related side effects.

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Section: Discussionmentioning

confidence: 99%

Glioblastoma is associated with extensive accelerated brain ageing

Ainslie

Klaver

Voshart

et al. 2022

Preprint

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“…Wild-type α-synuclein is unfolded and can be sequestered via many pathways, such as autophagy and CMA [ 54 ]. On the contrary, proteins that are encoded by mutant genes can misfold and begin a vicious cycle [ 55 ]. For example, overexpression of wild-type or mutant α-synuclein can compromise the degradation pathways ( Figure 1 ), causing abnormal buildup of α-synuclein that assembles, thus contributing to the formation of Lewy bodies in Parkinson disease brains [ 3 , 46 , 56 ].…”

Section: Role Of Autophagy In Parkinson Diseasementioning

confidence: 99%

Autophagy and Its Association with Genetic Mutations in Parkinson Disease

Erekat

2022

Med Sci Monit

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Parkinson disease is the second most common neurodegenerative disorder, affecting 0.1–0.2% of the general population. It is a progressive debilitating disorder caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta. It is characterized by motor and non-motor symptoms. Parkinson disease can be caused by mutations in genes that encode proteins involved in the autophagic process, resulting in impaired autophagy. Indeed, autophagy has been implicated in the pathogenesis of Parkinson disease, particularly because its impairment causes the buildup of proteins. Thus, this review aims to provide an overview of Parkinson disease-related genetic mutations and their association with autophagy impairment in Parkinson disease, which can be helpful in improving the understanding of the pathogenesis of Parkinson disease, illustrating the potential therapeutic implications of agents that can enhance autophagy in Parkinson disease. Additionally, we will highlight the essential need for the development of highly sensitive and specific assays for gene-based diagnostic biomarkers. Finally, we will provide an overview on the potential gene-based therapeutic approaches for Parkinson disease, which have been most advanced and are associated with the most common targets being alpha-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2), and glucocerebrosidase (GBA).

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“…As discussed, protein aggregation-induced DNA damage is rapidly emerging as a contributing factor in the aetiology of many age-related neurodegenerative disorders. Importantly, the relationship between protein homeostasis and genome stability is a two-way street-aggregation of specific proteins like amyloid-β, Tau, mutant Htt and α-synuclein can impact genome stability, but conversely, genome instability can also dramatically affect the proteome [133]. This is clearly exemplified by known genetic alterations in more than 30 human genes that are strongly associated with protein aggregation and disease [134].…”

Section: Dna Damage Leading To Loss Of Protein Quality Controlmentioning

confidence: 99%

Genome instability and loss of protein homeostasis: converging paths to neurodegeneration?

et al. 2021

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Genome instability and loss of protein homeostasis are hallmark events of age-related diseases that include neurodegeneration. Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are characterized by protein aggregation, while an impaired DNA damage response (DDR) as in many genetic DNA repair disorders leads to pronounced neuropathological features. It remains unclear to what degree these cellular events interconnect with each other in the development of neurological diseases. This review highlights how the loss of protein homeostasis and genome instability influence one other. We will discuss studies that illustrate this connection. DNA damage contributes to many neurodegenerative diseases, as shown by an increased level of DNA damage in patients, possibly due to the effects of protein aggregates on chromatin, the sequestration of DNA repair proteins and novel putative DNA repair functions. Conversely, genome stability is also important for protein homeostasis. For example, gene copy number variations and the loss of key DDR components can lead to marked proteotoxic stress. An improved understanding of how protein homeostasis and genome stability are mechanistically connected is needed and promises to lead to the development of novel therapeutic interventions.

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

Cited by 13 publications

References 247 publications

Glioblastoma is associated with extensive accelerated brain ageing

Glioblastoma is associated with extensive accelerated brain ageing

Autophagy and Its Association with Genetic Mutations in Parkinson Disease

Genome instability and loss of protein homeostasis: converging paths to neurodegeneration?

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