Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease

Aging Cell, Journal Year: 2019, Volume and Issue: 18(6)

Published: Aug. 20, 2019

Abstract Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease‐modifying treatments. Motor dysfunction results from loss of dopaminergic neurons substantia nigra pars compacta depletion dopamine nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays undeniable role complex progressive neurodegenerative cascade. This review will explore molecular factors that contribute to high steady‐state healthy during aging, how chemical environment renders susceptible damage disease. Contributing as pathogenic be discussed within context why therapeutic approaches targeting cellular redox activity disorder have, date, yielded little benefit. We present contemporary perspective on central contribution imbalance etiology argue improving our ability accurately measure stress, neurotransmission cell death pathways vivo crucial both development new therapies identification novel biomarkers.

Language: Английский

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Bidirectional Microglia–Neuron Communication in Health and Disease

Frontiers in Cellular Neuroscience, Journal Year: 2018, Volume and Issue: 12

Published: Sept. 27, 2018

Microglia are ramified cells that exhibit highly motile processes, which continuously survey the brain parenchyma and react to any insult CNS homeostasis. Although microglia have long been recognized as a crucial player in generating maintaining inflammatory responses CNS, now it has become clear, their function much more diverse, particularly healthy brain. The innate immune response phagocytosis represent only little segment of functional repertoire also includes maintenance biochemical homeostasis, neuronal circuit maturation during development experience- dependent remodeling circuits adult Being equipped by numerous receptors cell surface molecules can perform bidirectional interactions with other types CNS. There is accumulating evidence showing neurons inform about status thus capable controlling microglial activation motility while modulate activities. This review addresses topic: how communicate brain, including fractalkine signaling, secreted soluble factors extracellular vesicles. We summarize current state knowledge physiological role mature further highlight contribution pathologies such Alzheimer's Parkinson's disease, ischemia, traumatic injury, tumour well neuropsychiatric diseases (depression, bipolar disorder schizophrenia).

Language: Английский

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Glutamate-induced excitotoxicity in Parkinson's disease: The role of glial cells

Journal of Pharmacological Sciences, Journal Year: 2020, Volume and Issue: 144(3), P. 151 - 164

Published: Aug. 1, 2020

Glutamate is the major excitatory neurotransmitter in central nervous system. transmission efficiency depends on correct functionality and expression of a plethora receptors transporters, located both neurons glial cells. Of note, glutamate reuptake by dedicated transporters prevents its accumulation at synapse as well non-physiological spillover. Indeed, extracellular increase causes aberrant synaptic signaling leading to neuronal excitotoxicity death. Moreover, extrasynaptic diffusion strongly associated with glia reaction neuroinflammation. Glutamate-induced mainly linked an impaired ability cells respond glutamate, then this considered common hallmark many neurodegenerative diseases, including Parkinson's disease (PD). In review, we discuss function astrocytes microglia homeostasis, focusing how dysfunction glutamate-induced neurodegeneration PD.

Language: Английский

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Preterm birth and sustained inflammation: consequences for the neonate

Seminars in Immunopathology, Journal Year: 2020, Volume and Issue: 42(4), P. 451 - 468

Published: July 13, 2020

Abstract Almost half of all preterm births are caused or triggered by an inflammatory process at the feto-maternal interface resulting in labor rupture membranes with without chorioamnionitis (“first hit”). Preterm babies have highly vulnerable body surfaces and immature organ systems. They postnatally confronted a drastically altered antigen exposure including hospital-specific microbes, artificial devices, drugs, nutritional antigens, hypoxia hyperoxia (“second This is particular importance to extremely infants born before 28 weeks, as they not experienced important “third-trimester” adaptation processes tolerate maternal self-antigens. Instead balanced extrauterine life, delicate co-regulation between immune defense mechanisms immunosuppression (tolerance) allow microbiome establishment therefore often disturbed. Hence, predisposed sepsis but also several injurious conditions that can contribute onset perpetuation sustained inflammation (SI). continuing challenge clinicians involved care infants, SI regarded crucial mediator for mortality development morbidities infants. review will outline (i) role short-term consequences birth (ii) effect on long-term outcome.

Language: Английский

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Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer’s disease

Acta Neuropathologica Communications, Journal Year: 2021, Volume and Issue: 9(1)

Published: April 26, 2021

Abstract Alzheimer’s disease (AD) is the most common cause of age-related dementia. Increasing evidence suggests that neuroinflammation mediated by microglia and astrocytes contributes to progression severity in AD other neurodegenerative disorders. During progression, resident undergo proinflammatory activation, resulting an increased capacity convert resting reactive astrocytes. Therefore, are a major therapeutic target for blocking microglia-astrocyte activation could limit neurodegeneration AD. Here we report NLY01, engineered exedin-4, glucagon-like peptide-1 receptor (GLP-1R) agonist, selectively blocks β-amyloid (Aβ)-induced through GLP-1R inhibits formation as well preserves neurons models. In two transgenic mouse models (5xFAD 3xTg-AD), repeated subcutaneous administration NLY01 blocked microglia-mediated astrocyte conversion preserved neuronal viability, improved spatial learning memory. Our study indicates GLP-1 pathway plays critical role microglia-reactive associated effects primarily direct action on Aβ-induced + microglia, contributing inhibition reactivity. These results show targeting upregulated viable therapy

Language: Английский

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New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2698 - 2698

Published: Feb. 26, 2024

Oxidative stress (OS) and inflammation are two important well-studied pathological hallmarks of neurodegenerative diseases (NDDs). Due to elevated oxygen consumption, the high presence easily oxidizable polyunsaturated fatty acids weak antioxidant defenses, brain is particularly vulnerable oxidative injury. Uncertainty exists over whether these deficits contribute development NDDs or solely a consequence neuronal degeneration. Furthermore, linked, it known that OS can affect inflammatory response. In this review, we will overview last findings about pathways in principal NDDs. Moreover, focus more depth on amyotrophic lateral sclerosis (ALS) understand how anti-inflammatory antioxidants drugs have been used for treatment still incurable motor neuron (MN) disease. Finally, analyze past actual clinical trials future perspectives study mechanisms.

Language: Английский

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Pathogenesis of Parkinson’s Disease

Neurologic Clinics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Astrocytic Oxidative/Nitrosative Stress Contributes to Parkinson’s Disease Pathogenesis: The Dual Role of Reactive Astrocytes

Antioxidants, Journal Year: 2019, Volume and Issue: 8(8), P. 265 - 265

Published: Aug. 1, 2019

Parkinson’s disease (PD) is the second most common neurodegenerative worldwide; it characterized by dopaminergic neurodegeneration in substantia nigra pars compacta, but its etiology not fully understood. Astrocytes, a class of glial cells central nervous system (CNS), provide critical structural and metabolic support to neurons, growing evidence reveals that astrocytic oxidative nitrosative stress contributes PD pathogenesis. As astrocytes play role production antioxidants detoxification reactive oxygen nitrogen species (ROS/RNS), oxidative/nitrosative has emerged as mediator PD. Cellular inflammation induce astrogliosis, which initiates ROS/RNS may lead Although cause aberrant astrogliosis unknown, gene mutations environmental toxicants also contribute stress. In this review, we briefly discuss physiological functions Additionally, examine impact PD-related genes such α-synuclein, protein deglycase DJ-1( DJ-1), Parkin, PTEN-induced kinase 1 (PINK1) on function, highlight toxicants, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, manganese, paraquat, experimental models.

Language: Английский

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Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson’s Disease

Current Biology, Journal Year: 2020, Volume and Issue: 30(2), P. 276 - 291.e9

Published: Jan. 1, 2020

Language: Английский

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RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase–mediated centrosomal cohesion and ciliogenesis deficits

Human Molecular Genetics, Journal Year: 2019, Volume and Issue: 28(21), P. 3552 - 3568

Published: Aug. 15, 2019

Abstract Mutations in the LRRK2 kinase are most common cause of familial Parkinson’s disease, and variants increase risk for sporadic form disease. phosphorylates multiple RAB GTPases including RAB8A RAB10. Phosphorylated RAB10 is recruited to centrosome-localized RILPL1, which may interfere with ciliogenesis a disease-relevant context. Our previous studies indicate that centrosomal accumulation phosphorylated causes cohesion deficits dividing cells, peripheral patient-derived cells. Here, we show both RAB8 contribute deficits. Pathogenic not only phosho-RAB8 but also phospho-RAB10, effects on dependent RAB8, RILPL1. Conversely, pathogenic LRRK2-mediated defects correlate phospho-RAB8 phospho-RAB10. alterations observed as well primary astrocytes from mutant mice, reverted upon inhibition. These data suggest distinct cellular readouts same underlying phospho-RAB8/RAB10/RILPL1 nexus highlight possibility either and/or serve biomarkers LRRK2-related PD.

Language: Английский

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