International Journal of Molecular Sciences

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16 pages, 3560 KiB

Open AccessArticle

Oxidative DNA Damage and Cisplatin Neurotoxicity Is Exacerbated by Inhibition of OGG1 Glycosylase Activity and APE1 Endonuclease Activity in Sensory Neurons

by Adib Behrouzi, Hanyu Xia, Eric L. Thompson, Mark R. Kelley and Jill C. Fehrenbacher

Int. J. Mol. Sci. 2022, 23(3), 1909; https://doi.org/10.3390/ijms23031909 - 8 Feb 2022

Cited by 4 | Viewed by 3099

Abstract

Cisplatin can induce peripheral neuropathy, which is a common complication of anti-cancer treatment and negatively impacts cancer survivors during and after completion of treatment; therefore, the mechanisms by which cisplatin alters sensory neuronal function to elicit neuropathy are the subject of much investigation. [...] Read more.

Cisplatin can induce peripheral neuropathy, which is a common complication of anti-cancer treatment and negatively impacts cancer survivors during and after completion of treatment; therefore, the mechanisms by which cisplatin alters sensory neuronal function to elicit neuropathy are the subject of much investigation. Our previous work suggests that the DNA repair activity of APE1/Ref-1, the rate-limiting enzyme of the base excision repair (BER) pathway, is critical for neuroprotection against cisplatin. A specific role for 8-oxoguanine DNA glycosylase-1 (OGG1), the glycosylase that removes the most common oxidative DNA lesion, and putative coordination of OGG1 with APE1/Ref-1 in sensory neurons, has not been investigated. We investigated whether inhibiting OGG1 glycosylase activity with the small molecule inhibitor, TH5487, and/or APE1/Ref-1 endonuclease activity with APE Repair Inhibitor III would alter the neurotoxic effects of cisplatin in sensory neuronal cultures. Sensory neuron function was assessed by calcitonin gene-related peptide (CGRP) release, as a marker of sensitivity and by neurite outgrowth. Cisplatin altered neuropeptide release in an inverse U-shaped fashion, with low concentrations enhancing and higher concentrations diminishing CGRP release. Pretreatment with BER inhibitors exacerbated the functional effects of cisplatin and enhanced 8oxo-dG and adduct lesions in the presence of cisplatin. Our studies demonstrate that inhibition of OGG1 and APE1 endonuclease activity enhances oxidative DNA damage and exacerbates neurotoxicity, thus limiting oxidative DNA damage in sensory neurons that might alleviate cisplatin-induced neuropathy. Full article

(This article belongs to the Special Issue Genome Stability and Neurological Disease)

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19 pages, 1475 KiB

Open AccessArticle

Alzheimer’s Disease-Associated SNP rs708727 in SLC41A1 May Increase Risk for Parkinson’s Disease: Report from Enlarged Slovak Study

by Michal Cibulka, Maria Brodnanova, Marian Grendar, Jan Necpal, Jan Benetin, Vladimir Han, Egon Kurca, Vladimir Nosal, Matej Skorvanek, Branislav Vesely, Andrea Stanclova, Zora Lasabova, Zuzana Pös, Tomas Szemes, Stanislav Stuchlik, Milan Grofik and Martin Kolisek

Int. J. Mol. Sci. 2022, 23(3), 1604; https://doi.org/10.3390/ijms23031604 - 29 Jan 2022

Cited by 5 | Viewed by 2836

Abstract

SLC41A1 (A1) SNPs rs11240569 and rs823156 are associated with altered risk for Parkinson’s disease (PD), predominantly in Asian populations, and rs708727 has been linked to Alzheimer’s disease (AD). In this study, we have examined a potential association of the three aforementioned [...] Read more.

SLC41A1 (A1) SNPs rs11240569 and rs823156 are associated with altered risk for Parkinson’s disease (PD), predominantly in Asian populations, and rs708727 has been linked to Alzheimer’s disease (AD). In this study, we have examined a potential association of the three aforementioned SNPs and of rs9438393, rs56152218, and rs61822602 (all three lying in the A1 promoter region) with PD in the Slovak population. Out of the six tested SNPs, we have identified only rs708727 as being associated with an increased risk for PD onset in Slovaks. The minor allele (A) in rs708727 is associated with PD in dominant and completely over-dominant genetic models (OR_D = 1.36 (1.05–1.77), p = 0.02, and OR_COD = 1.34 (1.04–1.72), p = 0.02). Furthermore, the genotypic triplet GG_(rs708727) + AG_(rs823156) + CC_(rs61822602) might be clinically relevant despite showing a medium (h ≥ 0.5) size difference (h = 0.522) between the PD and the control populations. RandomForest modeling has identified the power of the tested SNPs for discriminating between PD-patients and the controls to be essentially zero. The identified association of rs708727 with PD in the Slovak population leads us to hypothesize that this A1 polymorphism, which is involved in the epigenetic regulation of the expression of the AD-linked gene PM20D1, is also involved in the pathoetiology of PD (or universally in neurodegeneration) through the same or similar mechanism as in AD. Full article

(This article belongs to the Special Issue Genome Stability and Neurological Disease)

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18 pages, 44409 KiB

Open AccessArticle

DRP1 Inhibition Rescues Mitochondrial Integrity and Excessive Apoptosis in CS-A Disease Cell Models

by Barbara Pascucci, Francesca Spadaro, Donatella Pietraforte, Chiara De Nuccio, Sergio Visentin, Paola Giglio, Eugenia Dogliotti and Mariarosaria D’Errico

Int. J. Mol. Sci. 2021, 22(13), 7123; https://doi.org/10.3390/ijms22137123 - 1 Jul 2021

Cited by 8 | Viewed by 2989

Abstract

Cockayne syndrome group A (CS-A) is a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. Cells derived from CS-A patients present as pathological hallmarks excessive oxidative stress, mitochondrial fragmentation and apoptosis associated with hyperactivation of the mitochondrial fission dynamin related [...] Read more.

Cockayne syndrome group A (CS-A) is a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. Cells derived from CS-A patients present as pathological hallmarks excessive oxidative stress, mitochondrial fragmentation and apoptosis associated with hyperactivation of the mitochondrial fission dynamin related protein 1 (DRP1). In this study, by using human cell models we further investigated the interplay between DRP1 and CSA and we determined whether pharmacological or genetic inhibition of DRP1 affects disease progression. Both reactive oxygen and nitrogen species are in excess in CS-A cells and when the mitochondrial translocation of DRP1 is inhibited a reduction of these species is observed together with a recovery of mitochondrial integrity and a significant decrease of apoptosis. This study indicates that the CSA-driven modulation of DRP1 pathway is key to control mitochondrial homeostasis and apoptosis and suggests DRP1 as a potential target in the treatment of CS patients. Full article

(This article belongs to the Special Issue Genome Stability and Neurological Disease)

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Review

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15 pages, 2503 KiB

Open AccessReview

The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment

by Arun Meyyazhagan, Haripriya Kuchi Bhotla, Manikantan Pappuswamy and Antonio Orlacchio

Int. J. Mol. Sci. 2022, 23(14), 7665; https://doi.org/10.3390/ijms23147665 - 11 Jul 2022

Cited by 14 | Viewed by 7828

Abstract

Inherited neurodegenerative pathology characterized by lower muscle tone and increasing spasticity in the lower limbs is termed hereditary spastic paraplegia (HSP). HSP is associated with changes in about 80 genes and their products involved in various biochemical pathways, such as lipid droplet formation, [...] Read more.

Inherited neurodegenerative pathology characterized by lower muscle tone and increasing spasticity in the lower limbs is termed hereditary spastic paraplegia (HSP). HSP is associated with changes in about 80 genes and their products involved in various biochemical pathways, such as lipid droplet formation, endoplasmic reticulum shaping, axon transport, endosome trafficking, and mitochondrial function. With the inheritance patterns of autosomal dominant, autosomal recessive, X-linked recessive, and mitochondrial inheritance, HSP is prevalent around the globe at a rate of 1–5 cases in every 100,000 individuals. Recent technology and medical interventions somewhat aid in recognizing and managing the malaise. However, HSP still lacks an appropriate and adequate therapeutic approach. Current therapies are based on the clinical manifestations observed in the patients, for example, smoothing the relaxant spastic muscle and physiotherapies. The limited clinical trial studies contribute to the absence of specific pharmaceuticals for HSPs. Our current work briefly explains the causative genes, epidemiology, underlying mechanism, and the management approach undertaken to date. We have also mentioned the latest approved drugs to summarise the available knowledge on therapeutic strategies for HSP. Full article

(This article belongs to the Special Issue Genome Stability and Neurological Disease)

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34 pages, 1046 KiB

Open AccessReview

DNA Double-Strand Breaks as Pathogenic Lesions in Neurological Disorders

by Vincent E. Provasek, Joy Mitra, Vikas H. Malojirao and Muralidhar L. Hegde

Int. J. Mol. Sci. 2022, 23(9), 4653; https://doi.org/10.3390/ijms23094653 - 22 Apr 2022

Cited by 13 | Viewed by 4424

Abstract

The damage and repair of DNA is a continuous process required to maintain genomic integrity. DNA double-strand breaks (DSBs) are the most lethal type of DNA damage and require timely repair by dedicated machinery. DSB repair is uniquely important to nondividing, post-mitotic cells [...] Read more.

The damage and repair of DNA is a continuous process required to maintain genomic integrity. DNA double-strand breaks (DSBs) are the most lethal type of DNA damage and require timely repair by dedicated machinery. DSB repair is uniquely important to nondividing, post-mitotic cells of the central nervous system (CNS). These long-lived cells must rely on the intact genome for a lifetime while maintaining high metabolic activity. When these mechanisms fail, the loss of certain neuronal populations upset delicate neural networks required for higher cognition and disrupt vital motor functions. Mammalian cells engage with several different strategies to recognize and repair chromosomal DSBs based on the cellular context and cell cycle phase, including homologous recombination (HR)/homology-directed repair (HDR), microhomology-mediated end-joining (MMEJ), and the classic non-homologous end-joining (NHEJ). In addition to these repair pathways, a growing body of evidence has emphasized the importance of DNA damage response (DDR) signaling, and the involvement of heterogeneous nuclear ribonucleoprotein (hnRNP) family proteins in the repair of neuronal DSBs, many of which are linked to age-associated neurological disorders. In this review, we describe contemporary research characterizing the mechanistic roles of these non-canonical proteins in neuronal DSB repair, as well as their contributions to the etiopathogenesis of selected common neurological diseases. Full article

(This article belongs to the Special Issue Genome Stability and Neurological Disease)

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27 pages, 3503 KiB

Open AccessReview

Genome Integrity and Neurological Disease

by Elle E. M. Scheijen and David M. Wilson III

Int. J. Mol. Sci. 2022, 23(8), 4142; https://doi.org/10.3390/ijms23084142 - 8 Apr 2022

Cited by 8 | Viewed by 2506

Abstract

Neurological complications directly impact the lives of hundreds of millions of people worldwide. While the precise molecular mechanisms that underlie neuronal cell loss remain under debate, evidence indicates that the accumulation of genomic DNA damage and consequent cellular responses can promote apoptosis and [...] Read more.

Neurological complications directly impact the lives of hundreds of millions of people worldwide. While the precise molecular mechanisms that underlie neuronal cell loss remain under debate, evidence indicates that the accumulation of genomic DNA damage and consequent cellular responses can promote apoptosis and neurodegenerative disease. This idea is supported by the fact that individuals who harbor pathogenic mutations in DNA damage response genes experience profound neuropathological manifestations. The review article here provides a general overview of the nervous system, the threats to DNA stability, and the mechanisms that protect genomic integrity while highlighting the connections of DNA repair defects to neurological disease. The information presented should serve as a prelude to the Special Issue “Genome Stability and Neurological Disease”, where experts discuss the role of DNA repair in preserving central nervous system function in greater depth. Full article

(This article belongs to the Special Issue Genome Stability and Neurological Disease)

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22 pages, 3095 KiB

Open AccessReview

Impact of Oxidative DNA Damage and the Role of DNA Glycosylases in Neurological Dysfunction

by Mirta Mittelstedt Leal de Sousa, Jing Ye, Luisa Luna, Gunn Hildrestrand, Karine Bjørås, Katja Scheffler and Magnar Bjørås

Int. J. Mol. Sci. 2021, 22(23), 12924; https://doi.org/10.3390/ijms222312924 - 29 Nov 2021

Cited by 4 | Viewed by 2687

Abstract

The human brain requires a high rate of oxygen consumption to perform intense metabolic activities, accounting for 20% of total body oxygen consumption. This high oxygen uptake results in the generation of free radicals, including reactive oxygen species (ROS), which, at physiological levels, [...] Read more.

The human brain requires a high rate of oxygen consumption to perform intense metabolic activities, accounting for 20% of total body oxygen consumption. This high oxygen uptake results in the generation of free radicals, including reactive oxygen species (ROS), which, at physiological levels, are beneficial to the proper functioning of fundamental cellular processes. At supraphysiological levels, however, ROS and associated lesions cause detrimental effects in brain cells, commonly observed in several neurodegenerative disorders. In this review, we focus on the impact of oxidative DNA base lesions and the role of DNA glycosylase enzymes repairing these lesions on brain function and disease. Furthermore, we discuss the role of DNA base oxidation as an epigenetic mechanism involved in brain diseases, as well as potential roles of DNA glycosylases in different epigenetic contexts. We provide a detailed overview of the impact of DNA glycosylases on brain metabolism, cognition, inflammation, tissue loss and regeneration, and age-related neurodegenerative diseases based on evidence collected from animal and human models lacking these enzymes, as well as post-mortem studies on patients with neurological disorders. Full article

(This article belongs to the Special Issue Genome Stability and Neurological Disease)

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17 pages, 1929 KiB

Open AccessReview

DNA Damage-Induced Neurodegeneration in Accelerated Ageing and Alzheimer’s Disease

by Heling Wang, Sofie Lautrup, Domenica Caponio, Jianying Zhang and Evandro F. Fang

Int. J. Mol. Sci. 2021, 22(13), 6748; https://doi.org/10.3390/ijms22136748 - 23 Jun 2021

Cited by 23 | Viewed by 4927

Abstract

DNA repair ensures genomic stability to achieve healthy ageing, including cognitive maintenance. Mutations on genes encoding key DNA repair proteins can lead to diseases with accelerated ageing phenotypes. Some of these diseases are xeroderma pigmentosum group A (XPA, caused by mutation of XPA [...] Read more.

DNA repair ensures genomic stability to achieve healthy ageing, including cognitive maintenance. Mutations on genes encoding key DNA repair proteins can lead to diseases with accelerated ageing phenotypes. Some of these diseases are xeroderma pigmentosum group A (XPA, caused by mutation of XPA), Cockayne syndrome group A and group B (CSA, CSB, and are caused by mutations of CSA and CSB, respectively), ataxia-telangiectasia (A-T, caused by mutation of ATM), and Werner syndrome (WS, with most cases caused by mutations in WRN). Except for WS, a common trait of the aforementioned progerias is neurodegeneration. Evidence from studies using animal models and patient tissues suggests that the associated DNA repair deficiencies lead to depletion of cellular nicotinamide adenine dinucleotide (NAD⁺), resulting in impaired mitophagy, accumulation of damaged mitochondria, metabolic derailment, energy deprivation, and finally leading to neuronal dysfunction and loss. Intriguingly, these features are also observed in Alzheimer’s disease (AD), the most common type of dementia affecting more than 50 million individuals worldwide. Further studies on the mechanisms of the DNA repair deficient premature ageing diseases will help to unveil the mystery of ageing and may provide novel therapeutic strategies for AD. Full article

(This article belongs to the Special Issue Genome Stability and Neurological Disease)

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23 pages, 2191 KiB

Open AccessReview

Nucleotide Excision Repair: From Molecular Defects to Neurological Abnormalities

by Yuliya Krasikova, Nadejda Rechkunova and Olga Lavrik

Int. J. Mol. Sci. 2021, 22(12), 6220; https://doi.org/10.3390/ijms22126220 - 9 Jun 2021

Cited by 25 | Viewed by 5112

Abstract

Nucleotide excision repair (NER) is the most versatile DNA repair pathway, which can remove diverse bulky DNA lesions destabilizing a DNA duplex. NER defects cause several autosomal recessive genetic disorders. Xeroderma pigmentosum (XP) is one of the NER-associated syndromes characterized by low efficiency [...] Read more.

Nucleotide excision repair (NER) is the most versatile DNA repair pathway, which can remove diverse bulky DNA lesions destabilizing a DNA duplex. NER defects cause several autosomal recessive genetic disorders. Xeroderma pigmentosum (XP) is one of the NER-associated syndromes characterized by low efficiency of the removal of bulky DNA adducts generated by ultraviolet radiation. XP patients have extremely high ultraviolet-light sensitivity of sun-exposed tissues, often resulting in multiple skin and eye cancers. Some XP patients develop characteristic neurodegeneration that is believed to derive from their inability to repair neuronal DNA damaged by endogenous metabolites. A specific class of oxidatively induced DNA lesions, 8,5′-cyclopurine-2′-deoxynucleosides, is considered endogenous DNA lesions mainly responsible for neurological problems in XP. Growing evidence suggests that XP is accompanied by defective mitophagy, as in primary mitochondrial disorders. Moreover, NER pathway is absent in mitochondria, implying that the mitochondrial dysfunction is secondary to nuclear NER defects. In this review, we discuss the current understanding of the NER molecular mechanism and focuses on the NER linkage with the neurological degeneration in patients with XP. We also present recent research advances regarding NER involvement in oxidative DNA lesion repair. Finally, we highlight how mitochondrial dysfunction may be associated with XP. Full article

(This article belongs to the Special Issue Genome Stability and Neurological Disease)

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11 pages, 576 KiB

Open AccessReview

DNA Homeostasis and Senescence: Lessons from the Naked Mole Rat

by Harvey Boughey, Mateusz Jurga and Sherif F. El-Khamisy

Int. J. Mol. Sci. 2021, 22(11), 6011; https://doi.org/10.3390/ijms22116011 - 2 Jun 2021

Cited by 5 | Viewed by 26706

Abstract

As we age, our bodies accrue damage in the form of DNA mutations. These mutations lead to the generation of sub-optimal proteins, resulting in inadequate cellular homeostasis and senescence. The build-up of senescent cells negatively affects the local cellular micro-environment and drives ageing [...] Read more.

As we age, our bodies accrue damage in the form of DNA mutations. These mutations lead to the generation of sub-optimal proteins, resulting in inadequate cellular homeostasis and senescence. The build-up of senescent cells negatively affects the local cellular micro-environment and drives ageing associated disease, including neurodegeneration. Therefore, limiting the accumulation of DNA damage is essential for healthy neuronal populations. The naked mole rats (NMR) are from eastern Africa and can live for over three decades in chronically hypoxic environments. Despite their long lifespan, NMRs show little to no biological decline, neurodegeneration, or senescence. Here, we discuss molecular pathways and adaptations that NMRs employ to maintain genome integrity and combat the physiological and pathological decline in organismal function. Full article

(This article belongs to the Special Issue Genome Stability and Neurological Disease)

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