Astrocyte dysfunction in Parkinson's disease: from the perspectives of transmitted α-synuclein and genetic modulation

Wang, Changjing; Yang, Tongtong; Liang, Meiyu; Xie, Jiawei; Song, Ning

doi:10.1186/s40035-021-00265-y

Cited by 32 publications

(15 citation statements)

References 177 publications

(221 reference statements)

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“…As reported by Garcia-Revilla et al (2022) [ 183 ] in several experimental models including rotenone and 6OHDA injections, the influence of general inflammation on central neurotoxic activity is well established. The different reactivity of astrocytes and microglia is important evidence that needs to be considered in the PD pathogenesis; the astrocyte dysfunction might contribute to the neurodegenerative process in synucleinopathies [ 184 , 185 ].…”

Section: Alpha-synuclein and Inflammationmentioning

confidence: 99%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

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Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson’s disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.

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Section: Alpha-synuclein and Inflammationmentioning

confidence: 99%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

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“…Furthermore, we demonstrate that LRRC37A2 expression may play a role in the detection of extracellular monomeric α-synuclein by astrocytes, and consequently impacts migration and tissue repair. α-synuclein has previously been identified as a stimulant for astrocytes [50], inducing a reactive state [51]. This mechanism was impaired in the context of reduced LRRC37A2 expression, indicating that appropriate detection and response to stimulants by astrocytes is likely a protective mechanism against neuronal death.…”

Section: Discussionmentioning

confidence: 98%

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Bowles

Pugh²,

Liu³

et al. 2022

Mol Neurodegeneration

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Background Parkinson’s disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. Methods To better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue. Results We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. Conclusion These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

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“…These data illustrate the influence of general inflammation on central α-synOs activity and the different reactivity of astrocytes and microglia to double-hit stimulation ( La Vitola et al, 2021 ). Both findings are important to orient the therapeutic strategy in PD and associated synucleinopathies; the control of general inflammation might influence progression in the early phase of the disease and the astrocyte dysfunction is part of the pathological events associated with the activity of α-synOs ( Chen et al, 2021 ; Wang et al, 2021 ).…”

Section: Oligomers and Inflammationmentioning

confidence: 99%

Oligomeropathies, inflammation and prion protein binding

2022

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The central role of oligomers, small soluble aggregates of misfolded proteins, in the pathogenesis of neurodegenerative disorders is recognized in numerous experimental conditions and is compatible with clinical evidence. To underline this concept, some years ago we coined the term oligomeropathies to define the common mechanism of action of protein misfolding diseases like Alzheimer, Parkinson or prion diseases. Using simple experimental conditions, with direct application of synthetic β amyloid or α-synuclein oligomers intraventricularly at micromolar concentrations, we could detect differences and similarities in the biological consequences. The two oligomer species affected cognitive behavior, neuronal dysfunction and cerebral inflammatory reactions with distinct mechanisms. In these experimental conditions the proposed mediatory role of cellular prion protein in oligomer activities was not confirmed. Together with oligomers, inflammation at different levels can be important early in neurodegenerative disorders; both β amyloid and α-synuclein oligomers induce inflammation and its control strongly affects neuronal dysfunction. This review summarizes our studies with β-amyloid or α-synuclein oligomers, also considering the potential curative role of doxycycline, a well-known antibiotic with anti-amyloidogenic and anti-inflammatory activities. These actions are analyzed in terms of the therapeutic prospects.

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Astrocyte dysfunction in Parkinson's disease: from the perspectives of transmitted α-synuclein and genetic modulation

Cited by 32 publications

References 177 publications

Alpha Synuclein: Neurodegeneration and Inflammation

Alpha Synuclein: Neurodegeneration and Inflammation

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Oligomeropathies, inflammation and prion protein binding

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