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

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 elus...

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Main Author: Bianca Marchetti
Format: Article
Language:English
Published: Elsevier 2020-09-01
Series:Redox Biology
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S2213231720308697
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author Bianca Marchetti
author_facet Bianca Marchetti
author_sort Bianca Marchetti
collection DOAJ
description 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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spelling doaj.art-3e257ee2f6d34b5ebb58e92e512d707a2022-12-21T17:31:31ZengElsevierRedox Biology2213-23172020-09-0136101664Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's diseaseBianca Marchetti0Department of Biomedical and Biotechnological Sciences (BIOMETEC), Pharmacology Section, Medical School, University of Catania, Via S. Sofia 65, 95125, Catania, Italy; Oasi Research Institute-IRCCS, Neuropharmacology Section, Via Conte Ruggero 73, 94018, Troina, EN, Italy; Department of Biomedical and Biotechnological Sciences (BIOMETEC), Pharmacology Section, Medical School, University of Catania, Via S. Sofia 65, 95125, Catania, Italy.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.http://www.sciencedirect.com/science/article/pii/S2213231720308697Glia-neuron crosstalkParkinson's diseaseGene-environment interactionsNrf2 signalingWnt signalingAgeing
spellingShingle Bianca Marchetti
Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease
Redox Biology
Glia-neuron crosstalk
Parkinson's disease
Gene-environment interactions
Nrf2 signaling
Wnt signaling
Ageing
title Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease
title_full Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease
title_fullStr Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease
title_full_unstemmed Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease
title_short Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease
title_sort nrf2 wnt resilience orchestrates rejuvenation of glia neuron dialogue in parkinson s disease
topic Glia-neuron crosstalk
Parkinson's disease
Gene-environment interactions
Nrf2 signaling
Wnt signaling
Ageing
url http://www.sciencedirect.com/science/article/pii/S2213231720308697
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