Poly (ADP-ribose) polymerase-1 as a promising drug target for neurodegenerative diseases

Thapa, Komal; Khan, Heena; Sharma, Upendra K.; Grewal, Amarjot Kaur; Singh, Thakur Gurjeet

doi:10.1016/j.lfs.2020.118975

Cited by 52 publications

(27 citation statements)

References 100 publications

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“…Given the link between TDP-43 pathology and DNA damage, it is possible that therapies that target the DDR may be widely applicable in ALS, such as PARP-1 inhibitors, which are known to inhibit neuronal death. However these approaches have not been evaluated clinically ( Thapa et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

DNA Damage, Defective DNA Repair, and Neurodegeneration in Amyotrophic Lateral Sclerosis

Konopka

Atkin

2022

Front. Aging Neurosci.

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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 FUS, SOD1, SETX, VCP, CCNF, and NEK1. Here we review recent evidence highlighting DNA damage and defective DNA repair as an important mechanism linked to neurodegeneration in ALS.

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Section: Discussionmentioning

confidence: 99%

DNA Damage, Defective DNA Repair, and Neurodegeneration in Amyotrophic Lateral Sclerosis

Konopka

Atkin

2022

Front. Aging Neurosci.

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“…It is a special form of “cell death” different from apoptosis. Parthanatos is involved in neuronal loss and nerve function damage in many neurodegenerative diseases, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and Parkinson’s disease (PD) [ 5 , 15 ]. Therefore, some PARP-1 inhibitors were considered as drug candidates for neurodegenerative diseases such as AD [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

14,15-EET Reduced Brain Injury from Cerebral Ischemia and Reperfusion via Suppressing Neuronal Parthanatos

Zhao

Tang

Chen

et al. 2021

IJMS

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To investigate the effect of 14,15-EET on the parthanatos in neurons induced by cerebral ischemia and reperfusion, middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen glucose deprivation/reoxygenation (OGD/R) were used to simulate cerebral ischemia reperfusion in vivo and in vitro, respectively. TTC staining and the Tunel method were used to detect cerebral infarct volume and neuronal apoptosis. Western blot and immunofluorescence were used to detect poly (ADP-ribose) polymerase-1 (PARP-1) activation and AIF nuclear translocation. The production of reactive oxygen species (ROS) and the expression of antioxidant genes were detected by Mito SOX, DCFH-DA and qPCR methods. MCAO/R increased cerebral infarct volume and neuronal apoptosis in mice, while 14,15-EET pretreatment increased cerebral infarct volume and neuronal apoptosis. OGD/R induced reactive oxygen species generation, PARP-1 cleavage, and AIF nuclear translocation in cortical neurons. 14,15-EET pretreatment could enhance the antioxidant gene expression of glutathione peroxidase (GSH-Px), heme oxygenase-1 (HO-1) and superoxide dismutase (SOD) in cortical neurons after ischemia and reperfusion. 14,15-EET inhibits the neuronal parthanatos induced by MCAO/R through upregulation of the expression of antioxidant genes and by reducing the generation of reactive oxygen species. This study advances the EET neuroprotection theory and provides a scientific basis for targeted clinical drugs that reduce neuronal parthanatos following cerebral ischemia and reperfusion.

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“…Parp1 activity is involved with many of the toxic aspects of PD. Elimination of Parp1 activity reduced degeneration of dopaminergic neurons and improved motor behavior for multiple PD models [140]. A role for Parp1 in PD extends beyond mouse models.…”

Section: Parkinson's Diseasementioning

confidence: 99%

NAD+ Metabolism and Diseases with Motor Dysfunction

Lundt

Ding

2021

Genes

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Neurodegenerative diseases result in the progressive deterioration of the nervous system, with motor and cognitive impairments being the two most observable problems. Motor dysfunction could be caused by motor neuron diseases (MNDs) characterized by the loss of motor neurons, such as amyotrophic lateral sclerosis and Charcot–Marie–Tooth disease, or other neurodegenerative diseases with the destruction of brain areas that affect movement, such as Parkinson’s disease and Huntington’s disease. Nicotinamide adenine dinucleotide (NAD+) is one of the most abundant metabolites in the human body and is involved with numerous cellular processes, including energy metabolism, circadian clock, and DNA repair. NAD+ can be reversibly oxidized-reduced or directly consumed by NAD+-dependent proteins. NAD+ is synthesized in cells via three different paths: the de novo, Preiss–Handler, or NAD+ salvage pathways, with the salvage pathway being the primary producer of NAD+ in mammalian cells. NAD+ metabolism is being investigated for a role in the development of neurodegenerative diseases. In this review, we discuss cellular NAD+ homeostasis, looking at NAD+ biosynthesis and consumption, with a focus on the NAD+ salvage pathway. Then, we examine the research, including human clinical trials, focused on the involvement of NAD+ in MNDs and other neurodegenerative diseases with motor dysfunction.

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Poly (ADP-ribose) polymerase-1 as a promising drug target for neurodegenerative diseases

Cited by 52 publications

References 100 publications

DNA Damage, Defective DNA Repair, and Neurodegeneration in Amyotrophic Lateral Sclerosis

DNA Damage, Defective DNA Repair, and Neurodegeneration in Amyotrophic Lateral Sclerosis

14,15-EET Reduced Brain Injury from Cerebral Ischemia and Reperfusion via Suppressing Neuronal Parthanatos

NAD+ Metabolism and Diseases with Motor Dysfunction

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