Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases

Translational Neurodegeneration, Год журнала: 2023, Номер 12(1)

Опубликована: Апрель 14, 2023

Abstract Redox homeostasis refers to the balance between production of reactive oxygen species (ROS) as well nitrogen (RNS), and their elimination by antioxidants. It is linked all important cellular activities oxidative stress a result imbalance pro-oxidants antioxidant species. Oxidative perturbs many activities, including processes that maintain integrity DNA. Nucleic acids are highly therefore particularly susceptible damage. The DNA damage response detects repairs these lesions. Efficient repair essential for maintaining viability, but they decline considerably during aging. deficiencies in increasingly described age-related neurodegenerative diseases, such Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis Huntington’s disease. Furthermore, has long been associated with conditions. Moreover, both redox dysregulation increase significantly aging, which biggest risk factor diseases. However, links dysfunction damage, joint contributions pathophysiology conditions, only just emerging. This review will discuss associations address increasing evidence an major source disorders. Understanding connections may facilitate better understanding disease mechanisms, ultimately lead design therapeutic strategies based on preventing

Язык: Английский

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Current State and Future Directions in the Therapy of ALS

Cells, Год журнала: 2023, Номер 12(11), С. 1523 - 1523

Опубликована: Май 31, 2023

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway unclear potentially diverse, finding suitable therapy slow down or possibly stop disease progression remains challenging. Varying by country Riluzole, Edaravone, Sodium phenylbutyrate/Taurursodiol are only drugs currently approved in ALS treatment for their moderate effect on progression. Even though curative options, able prevent progression, still unknown, recent breakthroughs, especially field of targeting genetic forms, raise hope improved care patients. In this review, we aim summarize current state therapy, including medication as well supportive discuss ongoing developments prospects field. Furthermore, highlight rationale behind intense research biomarkers testing feasible way improve classification patients towards personalized medicine.

Язык: Английский

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Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Апрель 20, 2023

Abstract Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing neurons. Human induced pluripotent stem cell-derived neurons (iPSMNs) offer a solution; however, studies have typically limited to underpowered cohorts. Here, we present comprehensive compendium 429 iPSMNs from 15 datasets, 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, identify robust upregulation p53 signalling in ALS both cord. activation is greatest C9orf72 repeat expansions but weakest SOD1 FUS mutations. depletion potentiates neuronal nuclei cell culture, thereby functionally linking depletion. tissue display enrichment splicing alterations, somatic mutations, gene fusions, possibly contributing the DNA damage response.

Язык: Английский

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DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(7), С. 6313 - 6313

Опубликована: Март 28, 2023

Parkinson’s disease (PD) is the second most common neurodegenerative around world; however, its pathogenesis remains unclear so far. Recent advances have shown that DNA damage and repair deficiency play an important role in pathophysiology of PD. There growing evidence suggesting involved propagation cellular PD, leading to neuropathology under different conditions. Here, we reviewed current work on First, outlined causes Second, described potential pathways by which mediates neurotoxicity PD discussed precise mechanisms drive these processes damage. In addition, looked ahead interventions targeting repair. Finally, based status research, key problems need be addressed future research were proposed.

Язык: Английский

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Molecular hallmarks of ageing in amyotrophic lateral sclerosis

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Март 2, 2024

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal, severely debilitating and rapidly progressing disorder affecting motor neurons in the brain, brainstem, spinal cord. Unfortunately, there are few effective treatments, thus remains critical need to find novel interventions that can mitigate against its effects. Whilst aetiology of ALS unclear, ageing major risk factor. Ageing slowly progressive process marked by functional decline an organism over lifespan. However, it unclear how promotes ALS. At molecular cellular level specific hallmarks characteristic normal ageing. These highly inter-related overlap significantly with each other. Moreover, whilst process, striking similarities at between these factors neurodegeneration Nine were originally proposed: genomic instability, loss telomeres, senescence, epigenetic modifications, dysregulated nutrient sensing, proteostasis, mitochondrial dysfunction, stem cell exhaustion, altered inter-cellular communication. recently (2023) expanded include dysregulation autophagy, inflammation dysbiosis. Hence, given latest updates hallmarks, their close association disease processes ALS, new examination relationship pathophysiology warranted. In this review, we describe possible mechanisms which impacts on neurodegenerative implicated therapeutic may arise from this.

Язык: Английский

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Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration

ACS Chemical Neuroscience, Год журнала: 2024, Номер 15(15), С. 2665 - 2694

Опубликована: Июль 12, 2024

Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by expanded cytosine-adenine-guanine (CAG) repeats encoding proteins with abnormally polyglutamine tract. A total nine polyQ have been identified, including Huntington's disease, six spinocerebellar ataxias, dentatorubral pallidoluysian atrophy (DRPLA), and spinal bulbar muscular (SBMA). The this class each considered rare, yet constitute the largest monogenic disorders. While subtype has its own causative gene, certain pathologic molecular attributes implicated in virtually all diseases, protein aggregation, proteolytic cleavage, neuronal dysfunction, transcription dysregulation, autophagy impairment, mitochondrial dysfunction. Although animal models disease available helping to understand their pathogenesis access disease-modifying therapies, there is neither cure nor prevention for these only symptomatic treatments available. In paper, we analyze data from CAS Content Collection summarize research progress diseases. We examine publication landscape area effort provide insights into current knowledge advances developments. review most discussed concepts assess strategies combat Finally, inspect clinical applications products against development pipelines. objective broad overview evolving regarding outline challenges, evaluate growth opportunities further efforts combating

Язык: Английский

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Role of Oxidative Stress in Blood–Brain Barrier Disruption and Neurodegenerative Diseases

Antioxidants, Год журнала: 2024, Номер 13(12), С. 1462 - 1462

Опубликована: Ноя. 28, 2024

Upregulation of reactive oxygen species (ROS) levels is a principal feature observed in the brains neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s (AD). In these diseases, oxidative stress can disrupt blood–brain barrier (BBB). This disruption allows neurotoxic plasma components, blood cells, pathogens to enter brain, leading increased ROS production, mitochondrial dysfunction, inflammation. Collectively, factors result protein modification, lipid peroxidation, DNA damage, and, ultimately, neural cell damage. this review article, we present mechanisms by which damage leads BBB breakdown brain diseases. Additionally, summarize potential therapeutic approaches aimed at reducing that contributes

Язык: Английский

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FUS Contributes to Nerve Injury-Induced Nociceptive Hypersensitivity by Activating NF-κB Pathway in Primary Sensory Neurons

Journal of Neuroscience, Год журнала: 2023, Номер 43(7), С. 1267 - 1278

Опубликована: Янв. 10, 2023

Dysregulation of pain-associated genes in the dorsal root ganglion (DRG) is considered to be a molecular basis neuropathic pain genesis. Fused sarcoma (FUS), DNA/RNA-binding protein, critical regulator gene expression. However, whether it contributes unknown. This study showed that peripheral nerve injury caused by fourth lumbar (L4) spinal ligation (SNL) or chronic constriction (CCI) sciatic produced marked increase expression FUS protein injured DRG neurons. Blocking this through microinjection adeno-associated virus (AAV) 5-expressing Fus shRNA into ipsilateral L4 mitigated SNL-induced nociceptive hypersensitivities both male and female mice. also alleviated increases levels phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) glial fibrillary acidic (GFAP) horn. Furthermore, mimicking AAV5 expressing full-length mRNA unilateral L3/4 DRGs elevations p-ERK1/2 GFAP horn, enhanced responses mechanical, heat cold stimuli, induced spontaneous on side mice absence SNL. Mechanistically, increased activated NF-κB signaling pathway promoting translocation p65 nucleus phosphorylation from Our results indicate likely activation primary sensory neurons.SIGNIFICANCE STATEMENT In present study, we reported fused upregulated following injury. upregulation responsible for injury-induced Because blocking alleviates hypersensitivity, participates may potential target management.

Язык: Английский

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Biochemical and Molecular Pathways in Neurodegenerative Diseases: An Integrated View

Cells, Год журнала: 2023, Номер 12(18), С. 2318 - 2318

Опубликована: Сен. 20, 2023

Neurodegenerative diseases (NDDs) like Alzheimer’s disease (AD), Parkinson’s (PD), and amyotrophic lateral sclerosis (ALS) are defined by a myriad of complex aetiologies. Understanding the common biochemical molecular pathologies among NDDs gives an opportunity to decipher overlapping numerous cross-talk mechanisms neurodegeneration. Numerous interrelated pathways lead progression We present evidence from past pieces literature for most usual global convergent hallmarks ageing, oxidative stress, excitotoxicity-induced calcium butterfly effect, defective proteostasis including chaperones, autophagy, mitophagy, proteosome networks, neuroinflammation. Herein, we applied holistic approach identify represent shared mechanism across NDDs. Further, believe that this could be helpful in identifying key modulators NDDs, with particular focus on AD, PD, ALS. Moreover, these concepts development diagnosis novel strategies diverse

Язык: Английский

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C9orf72 expansion creates the unstable folate-sensitive fragile site FRA9A

Deleted Journal, Год журнала: 2024, Номер 1(4)

Опубликована: Окт. 1, 2024

Abstract The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia autoimmune disorders. C9orf72Exp patients display hyperactive cGAS-STING-linked immune DNA damage responses, but source of immunostimulatory or damaged unknown. Here, we show in pre-symptomatic sclerosis-frontotemporal patient cells brains cause folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33 kb as highly compacted chromatin embedded an 8.2 Mb fragility zone spanning 9p21, encompassing 46 genes, making one largest sites. instability, heightened global- Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s Chr9-containing micronuclei, providing endogenous sources DNA. Cells from contained a rearranged FRA9A-expressing Chr9 Chr9-wide dysregulated expression. Somatic repeat instability sensitive folate deficiency. Age-dependent can be transferred CNS peripheral tissues transgenic mice, implicating source. Our results highlight unappreciated effects that trigger vitamin-sensitive chromosome fragility, adding structural variations disease-enriched 9p21 likely elsewhere.

Язык: Английский

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