Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide; it is characterized by dopaminergic neurodegeneration in the substantia nigra pars compacta, but its etiology is not fully understood. Astrocytes, a class of glial cells in the central nervous system (CNS), provide critical structural and metabolic support to neurons, but growing evidence reveals that astrocytic oxidative and nitrosative stress contributes to PD pathogenesis. As astrocytes play a critical role in the production of antioxidants and the detoxification of reactive oxygen and nitrogen species (ROS/RNS), astrocytic oxidative/nitrosative stress has emerged as a critical mediator of the etiology of PD. Cellular stress and inflammation induce reactive astrogliosis, which initiates the production of astrocytic ROS/RNS and may lead to oxidative/nitrosative stress and PD pathogenesis. Although the cause of aberrant reactive astrogliosis is unknown, gene mutations and environmental toxicants may also contribute to astrocytic oxidative/nitrosative stress. In this review, we briefly discuss the physiological functions of astrocytes and the role of astrocytic oxidative/nitrosative stress in PD pathogenesis. Additionally, we examine the impact of PD-related genes such as α-synuclein, protein deglycase DJ-1( DJ-1), Parkin, and PTEN-induced kinase 1 (PINK1) on astrocytic function, and highlight the impact of environmental toxicants, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, manganese, and paraquat, on astrocytic oxidative/nitrosative stress in experimental models.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the most prevalent movement disorder worldwide [1]
PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and often the presence of cytoplasmic protein aggregates known as Lewy bodies, which result in decreased neurotransmission and motor deficits [2]
These findings indicate that generation of RNS and nitric monoxide (NO)-mediated protein modification serve essential roles in the healthy human brain, but pathological conditions such as PD lead to the overproduction of RNS and aberrant
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the most prevalent movement disorder worldwide [1]. Reactive astrocytes respond to acute cellular stress and work to limit CNS damage, but chronic astrogliosis can result in the sustained production of ROS/RNS and the release of proinflammatory molecules, which promotes neuronal injury and neurotoxicity [13]. Astrocytes secrete endogenous antioxidants (such as glutathione (GSH) and superoxide dismutase (SODs)) and neurotrophic factors into the extracellular microenvironment and are responsible for detoxification of reactive oxygen and nitrogen species (ROS/RNS) produced as byproducts of metabolism. Chronic reactive astrogliosis leads to astrocytic oxidative/nitrosative stress, neuroinflammation, neuronal apoptosis, and PD pathogenesis. Exposure to environmental toxicants such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and manganese (Mn) may contribute to the induction of reactive astrogliosis and consequent astrocytic oxidative/nitrosative stress [15,16,17]. We review the impact of environmental toxicants, such as MPTP, rotenone, Mn, and paraquat, on astrocytic oxidative/nitrosative stress and consequent neuropathogenesis
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