Targeting Aged Astrocytes May Be a New Therapeutic Strategy in Parkinson's Disease

Scott, Kirsten M.; Williams‐Gray, Caroline H.

doi:10.1002/mds.27387

Cited by 6 publications

(9 citation statements)

References 4 publications

(11 reference statements)

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“…Senescent astrocytes are also more prominent in brain tissues from patients with other neurodegenerative diseases, such as Parkinson's disease (PD) (Chinta et al, 2018;Scott and Williams-Gray, 2018) and amyotrophic lateral sclerosis (ALS) (Turnquist et al, 2016;Vazquez-Villasenor et al, 2019). PD is the second most common age-related neurodegenerative disease, characterized by loss of neurons in the substantia nigra pars compacta (SNpc), accumulation of α-synuclein, and presence of intraneuronal proteinaceous cytoplasmic inclusions (Lewy bodies) (Dauer and Przedborski, 2003).…”

Section: Astrocyte Senescence and Other Neurodegenerative Diseasesmentioning

confidence: 99%

Astrocyte Senescence and Alzheimer’s Disease: A Review

Han

Zhang

Liu

et al. 2020

Front. Aging Neurosci.

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Astrocytes are the largest group of glial cells in the brain and participate in several essential functions of the central nervous system (CNS). Disruption of their normal physiological function can lead to metabolism disequilibrium and the pathology of CNS. As an important mechanism of aging, cellular senescence has been considered as a primary inducing factor of age-associated neurodegenerative disorders. Senescent astrocytes showed decreased normal physiological function and increased secretion of senescence-associated secretory phenotype (SASP) factors, which contribute to Aβ accumulation, tau hyperphosphorylation, and the deposition of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). Astrocyte senescence also leads to a number of detrimental effects, including induced glutamate excitotoxicity, impaired synaptic plasticity, neural stem cell loss, and blood-brain barrier (BBB) dysfunction. In this review article, we have summarized the growing findings regarding astrocyte senescence and its putative role in the pathologic progress of AD. Additionally, we also focus on the significance of targeting astrocyte senescence as a novel and feasible therapeutic approach for AD.

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Section: Astrocyte Senescence and Other Neurodegenerative Diseasesmentioning

confidence: 99%

Astrocyte Senescence and Alzheimer’s Disease: A Review

Han

Zhang

Liu

et al. 2020

Front. Aging Neurosci.

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“…While reactive astrocytes have emerged as an important contributor to pathogenesis [12,150], few studies have examined therapeutic approaches to attenuating astrocytic oxidative/nitrosative stress in PD. Salidroside, extracted from Rhodiola rosea , decreased ROS production and increased viability in a neuron–astrocyte co-culture model [151].…”

Section: Pharmacological Attenuation Of Astrocytic Oxidative/nitromentioning

confidence: 99%

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

et al. 2019

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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.

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“…In particular, midbrain astrocytes are uniquely positioned to drive neuroprotective and regenerative programs in PD. Therefore, targeting not only diseased neurons, but specifically manipulating astroglial cells may provide a new approach for drug development for the treatment of neurological diseases, as PD [ [293] , [294] , [295] , [296] , [297] , [298] , [299] ] ( Fig. 8 ).…”

Section: The Therapeutic Impact: a Glial Avenue For Nigrostriatal Resmentioning

confidence: 99%

“…The possibility of modifying the pathologic brain environment by utilizing the neurotrophic properties of astrocytes is being actively pursued using different approaches, including derivation of astrocyte differentiated from NSCs or hiPSC sources, or conversion of fibroblasts directly into astrocytes, astrocyte co-transplantaion and astrocyte reprogramming [ [293] , [294] , [295] , [296] , [297] , [298] , [299] ]. Genetic manipulation of astrocytes to deliver at the location of active neuropathology potential neuroprotective molecules was studied by different authors Gene therapy approaches for PD can deliver neurotrophic factors such as GDNF or neurturin via neuronal transgene expression.…”

Section: The Therapeutic Impact: a Glial Avenue For Nigrostriatal Resmentioning

confidence: 99%

Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease

Marchetti

2020

Redox Biology

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Oxidative stress and inflammation have long been recognized to contribute to Parkinson's disease (PD), a common movement disorder characterized by the selective loss of midbrain dopaminergic neurons (mDAn) of the substantia nigra pars compacta (SNpc). The causes and mechanisms still remain elusive, but a complex interplay between several genes and a number of interconnected environmental factors, are chiefly involved in mDAn demise, as they intersect the key cellular functions affected in PD, such as the inflammatory response, mitochondrial, lysosomal, proteosomal and autophagic functions. Nuclear factor erythroid 2 -like 2 ( NFE2L2/Nrf2 ), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless ( Wnt ) /β-catenin signaling cascade, a vital pathway for mDAn neurogenesis and neuroprotection, emerge as critical intertwinned actors in mDAn physiopathology, as a decline of an Nrf2/Wnt/β-catenin prosurvival axis with age underlying PD mutations and a variety of noxious environmental exposures drive PD neurodegeneration. Unexpectedly, astrocytes, the so-called “ star-shaped ” cells, harbouring an arsenal of “beneficial” and “harmful” molecules represent the turning point in the physiopathological and therapeutical scenario of PD. Fascinatingly, “ astrocyte's fil rouge” brings back to Nrf2/Wnt resilience, as boosting the Nrf2/Wnt resilience program rejuvenates astrocytes, in turn (i) mitigating nigrostriatal degeneration of aged mice, (ii) reactivating neural stem progenitor cell proliferation and neuron differentiation in the brain and (iii) promoting a beneficial immunomodulation via bidirectional communication with mDAns. Then, through resilience of Nrf2/Wnt/β-catenin anti-ageing, prosurvival and proregenerative molecular programs, it seems possible to boost the inherent endogenous self-repair mechanisms. Here, the cellular and molecular aspects as well as the therapeutical options for rejuvenating glia-neuron dialogue will be discussed together with major glial-derived mechanisms and therapies that will be fundamental to the identification of novel diagnostic tools and treatments for neurodegenerative diseases (NDs), to fight ageing and nigrostriatal DAergic degeneration and promote functional recovery.

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Targeting Aged Astrocytes May Be a New Therapeutic Strategy in Parkinson's Disease

Cited by 6 publications

References 4 publications

Astrocyte Senescence and Alzheimer’s Disease: A Review

Astrocyte Senescence and Alzheimer’s Disease: A Review

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

Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease

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