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  1. Article: The Role of DNA Damage in Neural Plasticity in Physiology and Neurodegeneration.

    Konopka, Anna / Atkin, Julie D

    Frontiers in cellular neuroscience

    2022  Volume 16, Page(s) 836885

    Abstract: Damage to DNA is generally considered to be a harmful process associated with aging and aging-related disorders such as neurodegenerative diseases that involve the selective death of specific groups of neurons. However, recent studies have provided ... ...

    Abstract Damage to DNA is generally considered to be a harmful process associated with aging and aging-related disorders such as neurodegenerative diseases that involve the selective death of specific groups of neurons. However, recent studies have provided evidence that DNA damage and its subsequent repair are important processes in the physiology and normal function of neurons. Neurons are unique cells that form new neural connections throughout life by growth and re-organisation in response to various stimuli. This "plasticity" is essential for cognitive processes such as learning and memory as well as brain development, sensorial training, and recovery from brain lesions. Interestingly, recent evidence has suggested that the formation of double strand breaks (DSBs) in DNA, the most toxic form of damage, is a physiological process that modifies gene expression during normal brain activity. Together with subsequent DNA repair, this is thought to underlie neural plasticity and thus control neuronal function. Interestingly, neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington's disease, manifest by a decline in cognitive functions, which are governed by plasticity. This suggests that DNA damage and DNA repair processes that normally function in neural plasticity may contribute to neurodegeneration. In this review, we summarize current understanding about the relationship between DNA damage and neural plasticity in physiological conditions, as well as in the pathophysiology of neurodegenerative diseases.
    Language English
    Publishing date 2022-06-23
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2452963-1
    ISSN 1662-5102
    ISSN 1662-5102
    DOI 10.3389/fncel.2022.836885
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: DNA Damage, Defective DNA Repair, and Neurodegeneration in Amyotrophic Lateral Sclerosis.

    Konopka, Anna / Atkin, Julie D

    Frontiers in aging neuroscience

    2022  Volume 14, Page(s) 786420

    Abstract: DNA is under constant attack from both endogenous and exogenous sources, and when damaged, specific cellular signalling pathways respond, collectively termed the "DNA damage response." Efficient DNA repair processes are essential for cellular viability, ... ...

    Abstract DNA is under constant attack from both endogenous and exogenous sources, and when damaged, specific cellular signalling pathways respond, collectively termed the "DNA damage response." Efficient DNA repair processes are essential for cellular viability, although they decline significantly during aging. Not surprisingly, DNA damage and defective DNA repair are now increasingly implicated in age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS affects both upper and lower motor neurons in the brain, brainstem and spinal cord, leading to muscle wasting due to denervation. DNA damage is increasingly implicated in the pathophysiology of ALS, and interestingly, the number of DNA damage or repair proteins linked to ALS is steadily growing. This includes TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein that is present in a pathological form in almost all (97%) cases of ALS. Hence TDP-43 pathology is central to neurodegeneration in this condition. Fused in Sarcoma (FUS) bears structural and functional similarities to TDP-43 and it also functions in DNA repair. Chromosome 9 open reading frame 72 (C9orf72) is also fundamental to ALS because mutations in C9orf72 are the most frequent genetic cause of both ALS and related condition frontotemporal dementia, in European and North American populations. Genetic variants encoding other proteins involved in the DNA damage response (DDR) have also been described in ALS, including
    Language English
    Publishing date 2022-04-27
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2558898-9
    ISSN 1663-4365
    ISSN 1663-4365
    DOI 10.3389/fnagi.2022.786420
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  3. Article ; Online: The Mitochondrial-associated ER membrane (MAM) compartment and its dysregulation in Amyotrophic Lateral Sclerosis (ALS).

    Parakh, Sonam / Atkin, Julie D

    Seminars in cell & developmental biology

    2021  Volume 112, Page(s) 105–113

    Abstract: The endoplasmic reticulum (ER) and mitochondria connect at multiple contact sites to form a unique cellular compartment, termed the 'mitochondria-associated ER membranes' (MAMs). MAMs are hubs for signalling pathways that regulate cellular homeostasis ... ...

    Abstract The endoplasmic reticulum (ER) and mitochondria connect at multiple contact sites to form a unique cellular compartment, termed the 'mitochondria-associated ER membranes' (MAMs). MAMs are hubs for signalling pathways that regulate cellular homeostasis and survival, metabolism, and sensitivity to apoptosis. MAMs are therefore involved in vital cellular functions, but they are dysregulated in several human diseases. Whilst MAM dysfunction is increasingly implicated in the pathogenesis of neurodegenerative diseases, its role in amyotrophic lateral sclerosis (ALS) is poorly understood. However, in ALS both ER and mitochondrial dysfunction are well documented pathophysiological events. Moreover, alterations to lipid metabolism in neurons regulate processes linked to neurodegenerative diseases, and a link between dysfunction of lipid metabolism and ALS has also been proposed. In this review we discuss the structural and functional relevance of MAMs in ALS and how targeting MAM could be therapeutically beneficial in this disorder.
    MeSH term(s) Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Apoptosis/genetics ; Endoplasmic Reticulum/genetics ; Endoplasmic Reticulum/metabolism ; Humans ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Mitochondrial Membranes/pathology ; Muscular Dystrophies/genetics ; Muscular Dystrophies/metabolism ; Muscular Dystrophies/pathology
    Language English
    Publishing date 2021-03-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1312473-0
    ISSN 1096-3634 ; 1084-9521
    ISSN (online) 1096-3634
    ISSN 1084-9521
    DOI 10.1016/j.semcdb.2021.02.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2918: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Molecular hallmarks of ageing in amyotrophic lateral sclerosis.

    Jagaraj, Cyril Jones / Shadfar, Sina / Kashani, Sara Assar / Saravanabavan, Sayanthooran / Farzana, Fabiha / Atkin, Julie D

    Cellular and molecular life sciences : CMLS

    2024  Volume 81, Issue 1, Page(s) 111

    Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal, severely debilitating and rapidly progressing disorder affecting motor neurons in the brain, brainstem, and spinal cord. Unfortunately, there are few effective treatments, thus there remains a critical need ...

    Abstract Amyotrophic lateral sclerosis (ALS) is a fatal, severely debilitating and rapidly progressing disorder affecting motor neurons in the brain, brainstem, and spinal cord. Unfortunately, there are few effective treatments, thus there remains a critical need to find novel interventions that can mitigate against its effects. Whilst the aetiology of ALS remains unclear, ageing is the major risk factor. Ageing is a slowly progressive process marked by functional decline of an organism over its lifespan. However, it remains unclear how ageing promotes the risk of ALS. At the molecular and cellular level there are specific hallmarks characteristic of normal ageing. These hallmarks are highly inter-related and overlap significantly with each other. Moreover, whilst ageing is a normal process, there are striking similarities at the molecular level between these factors and neurodegeneration in ALS. Nine ageing hallmarks were originally proposed: genomic instability, loss of telomeres, senescence, epigenetic modifications, dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion, and altered inter-cellular communication. However, these were recently (2023) expanded to include dysregulation of autophagy, inflammation and dysbiosis. Hence, given the latest updates to these hallmarks, and their close association to disease processes in ALS, a new examination of their relationship to pathophysiology is warranted. In this review, we describe possible mechanisms by which normal ageing impacts on neurodegenerative mechanisms implicated in ALS, and new therapeutic interventions that may arise from this.
    MeSH term(s) Humans ; Amyotrophic Lateral Sclerosis/genetics ; Longevity ; Autophagy/genetics ; Brain
    Language English
    Publishing date 2024-03-02
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 1358415-7
    ISSN 1420-9071 ; 1420-682X
    ISSN (online) 1420-9071
    ISSN 1420-682X
    DOI 10.1007/s00018-024-05164-9
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 195: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article: Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases.

    Shadfar, Sina / Parakh, Sonam / Jamali, Md Shafi / Atkin, Julie D

    Translational neurodegeneration

    2023  Volume 12, Issue 1, Page(s) 18

    Abstract: Redox homeostasis refers to the balance between the production of reactive oxygen species (ROS) as well as reactive nitrogen species (RNS), and their elimination by antioxidants. It is linked to all important cellular activities and oxidative stress is a ...

    Abstract Redox homeostasis refers to the balance between the production of reactive oxygen species (ROS) as well as reactive nitrogen species (RNS), and their elimination by antioxidants. It is linked to all important cellular activities and oxidative stress is a result of imbalance between pro-oxidants and antioxidant species. Oxidative stress perturbs many cellular activities, including processes that maintain the integrity of DNA. Nucleic acids are highly reactive and therefore particularly susceptible to damage. The DNA damage response detects and repairs these DNA lesions. Efficient DNA repair processes are therefore essential for maintaining cellular viability, but they decline considerably during aging. DNA damage and deficiencies in DNA repair are increasingly described in age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Furthermore, oxidative stress has long been associated with these conditions. Moreover, both redox dysregulation and DNA damage increase significantly during aging, which is the biggest risk factor for neurodegenerative diseases. However, the links between redox dysfunction and DNA damage, and their joint contributions to pathophysiology in these conditions, are only just emerging. This review will discuss these associations and address the increasing evidence for redox dysregulation as an important and major source of DNA damage in neurodegenerative disorders. Understanding these connections may facilitate a better understanding of disease mechanisms, and ultimately lead to the design of better therapeutic strategies based on preventing both redox dysregulation and DNA damage.
    MeSH term(s) Humans ; Neurodegenerative Diseases/drug therapy ; Oxidative Stress/genetics ; Oxidation-Reduction ; Reactive Oxygen Species/therapeutic use ; Antioxidants/therapeutic use ; DNA Damage/genetics
    Chemical Substances Reactive Oxygen Species ; Antioxidants
    Language English
    Publishing date 2023-04-14
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2653701-1
    ISSN 2047-9158
    ISSN 2047-9158
    DOI 10.1186/s40035-023-00350-4
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  6. Article: Editorial: Defective DNA damage response-Repair axis in post-mitotic neurons in human health and neurodegenerative diseases.

    Konopka, Anna / Atkin, Julie D / Mitra, Joy

    Frontiers in cellular neuroscience

    2022  Volume 16, Page(s) 1009760

    Language English
    Publishing date 2022-08-23
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2452963-1
    ISSN 1662-5102
    ISSN 1662-5102
    DOI 10.3389/fncel.2022.1009760
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  7. Article ; Online: The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases.

    Shadfar, Sina / Brocardo, Mariana / Atkin, Julie D

    International journal of molecular sciences

    2022  Volume 23, Issue 5

    Abstract: Human cells are exposed to numerous exogenous and endogenous insults every day. Unlike other molecules, DNA cannot be replaced by resynthesis, hence damage to DNA can have major consequences for the cell. The DNA damage response contains overlapping ... ...

    Abstract Human cells are exposed to numerous exogenous and endogenous insults every day. Unlike other molecules, DNA cannot be replaced by resynthesis, hence damage to DNA can have major consequences for the cell. The DNA damage response contains overlapping signalling networks that repair DNA and hence maintain genomic integrity, and aberrant DNA damage responses are increasingly described in neurodegenerative diseases. Furthermore, DNA repair declines during aging, which is the biggest risk factor for these conditions. If unrepaired, the accumulation of DNA damage results in death to eliminate cells with defective genomes. This is particularly important for postmitotic neurons because they have a limited capacity to proliferate, thus they must be maintained for life. Neuronal death is thus an important process in neurodegenerative disorders. In addition, the inability of neurons to divide renders them susceptible to senescence or re-entry to the cell cycle. The field of cell death has expanded significantly in recent years, and many new mechanisms have been described in various cell types, including neurons. Several of these mechanisms are linked to DNA damage. In this review, we provide an overview of the cell death pathways induced by DNA damage that are relevant to neurons and discuss the possible involvement of these mechanisms in neurodegenerative conditions.
    MeSH term(s) DNA/metabolism ; DNA Damage ; DNA Repair ; Humans ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Neurons/metabolism
    Chemical Substances DNA (9007-49-2)
    Language English
    Publishing date 2022-02-24
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms23052484
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  8. Article: Emerging Evidence Highlighting the Importance of Redox Dysregulation in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS).

    Jagaraj, Cyril Jones / Parakh, Sonam / Atkin, Julie D

    Frontiers in cellular neuroscience

    2021  Volume 14, Page(s) 581950

    Abstract: The cellular redox state, or balance between cellular oxidation and reduction reactions, serves as a vital antioxidant defence system that is linked to all important cellular activities. Redox regulation is therefore a fundamental cellular process for ... ...

    Abstract The cellular redox state, or balance between cellular oxidation and reduction reactions, serves as a vital antioxidant defence system that is linked to all important cellular activities. Redox regulation is therefore a fundamental cellular process for aerobic organisms. Whilst oxidative stress is well described in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), other aspects of redox dysfunction and their contributions to pathophysiology are only just emerging. ALS is a fatal neurodegenerative disease affecting motor neurons, with few useful treatments. Hence there is an urgent need to develop more effective therapeutics in the future. Here, we discuss the increasing evidence for redox dysregulation as an important and primary contributor to ALS pathogenesis, which is associated with multiple disease mechanisms. Understanding the connection between redox homeostasis, proteins that mediate redox regulation, and disease pathophysiology in ALS, may facilitate a better understanding of disease mechanisms, and lead to the design of better therapeutic strategies.
    Language English
    Publishing date 2021-02-18
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452963-1
    ISSN 1662-5102
    ISSN 1662-5102
    DOI 10.3389/fncel.2020.581950
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  9. Article ; Online: Is cytoplasmic FUS a feature of all ALS?

    Vidal, Marta / Atkin, Julie D

    Brain : a journal of neurology

    2019  Volume 142, Issue 9, Page(s) 2546–2549

    MeSH term(s) Amyotrophic Lateral Sclerosis ; Cytoplasm ; Humans ; RNA-Binding Protein FUS
    Chemical Substances FUS protein, human ; RNA-Binding Protein FUS
    Language English
    Publishing date 2019-08-30
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awz256
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    In stock of ZB MED Cologne/Königswinter

    Ui II Zs.26: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  10. Article: Dysfunction of Optineurin in Amyotrophic Lateral Sclerosis and Glaucoma.

    Toth, Reka P / Atkin, Julie D

    Frontiers in immunology

    2018  Volume 9, Page(s) 1017

    Abstract: Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and glaucoma, affect millions of people worldwide. ALS is caused by the loss of motor neurons in the spinal cord, brainstem, and brain, and genetic ... ...

    Abstract Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and glaucoma, affect millions of people worldwide. ALS is caused by the loss of motor neurons in the spinal cord, brainstem, and brain, and genetic mutations are responsible for 10% of all ALS cases. Glaucoma is characterized by the loss of retinal ganglion cells and is the most common cause of irreversible blindness. Interestingly, mutations in
    MeSH term(s) Amyotrophic Lateral Sclerosis/genetics ; Animals ; Autophagy ; Glaucoma/genetics ; Humans ; Mice ; Mutation ; Transcription Factor TFIIIA/genetics ; Transcription Factor TFIIIA/physiology
    Chemical Substances OPTN protein, human ; Transcription Factor TFIIIA
    Language English
    Publishing date 2018-05-23
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2018.01017
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