TNF-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration

Russ, Kaspar; Teku, Gabriel; Bousset, Luc; Redeker, Virginie; Piel, Sara; Savchenko, Ekaterina; Pomeshchik, Yuriy; Savistchenko, Jimmy; Stummann, Tina C.; Azevedo, Carla; Collin, Anna; Goldwurm, Stefano; Fog, Karina; Elmér, Eskil; Vihinen, Mauno; Melki, Ronald; Roybon, Laurent

doi:10.1016/j.celrep.2021.108895

Cited by 37 publications

(36 citation statements)

References 45 publications

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“…We used hPSC-derived forebrain astrocyte model (hASTRO) meaning astrocytes at D95 of differentiation in vitro (Peteri et al, 2020) to study putative alterations of human FXS astrocytes (Figure 1a). Differentiation of astrocytes followed the developmental processes of astrocytes from neuroepithelial induction and regional patterning using morphogens to progenitor expansion and astrocyte specification/maturation (Russ et al, 2021). We monitored the differentiation of isogenic FXS and control hESC-derived cells by RNA-seq transcriptomic analysis at D0, D12, D30, D60, and D95 of differentiation (Figure 1a).…”

Section: Differentiation Of Astrocytes Modeling Fxsmentioning

confidence: 99%

Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Peteri

Pitkonen

Toma

et al. 2021

Glia

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The function of astrocytes intertwines with the extracellular matrix, whose neuron and glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities have been reported in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We compared human FXS and control astrocytes generated from human induced pluripotent stem cells and we found increased expression of urokinase plasminogen activator (uPA), which modulates degradation of extracellular matrix. Several pathways associated with uPA and its receptor function were activated in FXS astrocytes.Levels of uPA were also increased in conditioned medium collected from FXS hiPSCderived astrocyte cultures and correlated inversely with intracellular Ca 2+ responses to activation of L-type voltage-gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB within the docking site for the phospholipase-Cγ1 (PLCγ1), indicating effects of uPA on neuronal plasticity. Gene expression changes during neuronal differentiation preceding astrogenesis likely contributed to properties of astrocytes with FXS-specific alterations that showed specificity by not affecting differentiation of adenosine triphosphate (ATP)-responsive astrocyte Ulla-Kaisa Peteri and Juho Pitkonen contributed equally to this study.

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Section: Differentiation Of Astrocytes Modeling Fxsmentioning

confidence: 99%

Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Peteri

Pitkonen

Toma

et al. 2021

Glia

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“…Similar to the situation in neurons, mitochondrial respiration in these cells was impaired in response to a-SYN exposure. This effect was even more pronounced in PD patient astrocytes harboring PRKN mutations (141). Beyond DAMPs of neuronal (or even astroglial) origin, molecules released from microglia can initiate signaling cascades that mediate astrocyte reactivity (131).…”

Section: Astrocytes and Mitochondria In Inflammationmentioning

confidence: 99%

Astrocyte-Neuron Metabolic Crosstalk in Neurodegeneration: A Mitochondrial Perspective

2021

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Converging evidence made clear that declining brain energetics contribute to aging and are implicated in the initiation and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Indeed, both pathologies involve instances of hypometabolism of glucose and oxygen in the brain causing mitochondrial dysfunction, energetic failure and oxidative stress. Importantly, recent evidence suggests that astrocytes, which play a key role in supporting neuronal function and metabolism, might contribute to the development of neurodegenerative diseases. Therefore, exploring how the neuro-supportive role of astrocytes may be impaired in the context of these disorders has great therapeutic potential. In the following, we will discuss some of the so far identified features underlining the astrocyte-neuron metabolic crosstalk. Thereby, special focus will be given to the role of mitochondria. Furthermore, we will report on recent advancements concerning iPSC-derived models used to unravel the metabolic contribution of astrocytes to neuronal demise. Finally, we discuss how mitochondrial dysfunction in astrocytes could contribute to inflammatory signaling in neurodegenerative diseases.

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“…Although α-syn could undoubtedly induce a proinflammatory phenotype in astrocytes, it causes production of relatively lower levels of proinflammatory cytokines than does TNF-α treatment [ 52 ]. Adaptably, astrocytes with accumulated α-syn have been revealed with a novel role as antigen-presenting cells in chronic neuroinflammation in PD.…”

Section: Inflammatory Responsementioning

confidence: 99%

“…Consistent with this hypothesis, high-molecular-weight α-syn fibrils have been found to facilitate the acquisition of a reactive antigen (cross)-presenting phenotype by human iPSC-derived astrocytes, with upregulation of MHC gene expression and increased numbers of human leukocyte antigen (HLA) molecules at the cell surface. Small peptides derived from α-syn fibril degradation in astrocytes, rather than α-syn monomers, interact with MHC-II proteins and induce relocation of MHC molecules to the cell surface [ 52 ]. Interestingly, co-treatment of astrocytes with TNF-α and α-syn fibrils significantly decreased the effect of exposure to TNF-α or to α-syn fibrils alone, suggesting that TNF-α and α-syn fibrils compete to drive the immune reactive response of astrocytes to a proinflammatory phenotype or an antigen-presenting phenotype [ 52 ].…”

Section: Inflammatory Responsementioning

confidence: 99%

“…Small peptides derived from α-syn fibril degradation in astrocytes, rather than α-syn monomers, interact with MHC-II proteins and induce relocation of MHC molecules to the cell surface [ 52 ]. Interestingly, co-treatment of astrocytes with TNF-α and α-syn fibrils significantly decreased the effect of exposure to TNF-α or to α-syn fibrils alone, suggesting that TNF-α and α-syn fibrils compete to drive the immune reactive response of astrocytes to a proinflammatory phenotype or an antigen-presenting phenotype [ 52 ].…”

Section: Inflammatory Responsementioning

confidence: 99%

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

Wang

Yang

Liang

et al. 2021

Transl Neurodegener

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Parkinson’s disease (PD) is a common neurodegenerative disorder that primarily affects the elderly. While the etiology of PD is likely multifactorial with the involvement of genetic, environmental, aging and other factors, α-synuclein (α-syn) pathology is a pivotal mechanism underlying the development of PD. In recent years, astrocytes have attracted considerable attention in the field. Although astrocytes perform a variety of physiological functions in the brain, they are pivotal mediators of α-syn toxicity since they internalize α-syn released from damaged neurons, and this triggers an inflammatory response, protein degradation dysfunction, mitochondrial dysfunction and endoplasmic reticulum stress. Astrocytes are indispensable coordinators in the background of several genetic mutations, including PARK7, GBA1, LRRK2, ATP13A2, PINK1, PRKN and PLA2G6. As the most abundant glial cells in the brain, functional astrocytes can be replenished and even converted to functional neurons. In this review, we discuss astrocyte dysfunction in PD with an emphasis on α-syn toxicity and genetic modulation and conclude that astrocyte replenishment is a valuable therapeutic approach in PD.

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TNF-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration

Cited by 37 publications

References 45 publications

Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Astrocyte-Neuron Metabolic Crosstalk in Neurodegeneration: A Mitochondrial Perspective

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

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