Unique signatures of stress-induced senescent human astrocytes

Simmnacher, Katrin; Krach, Florian; Schneider, Yanni; Alecu, Julian E.; Mautner, Lena; Klein, Paulina; Roybon, Laurent; Prots, Iryna; Xiang, Wei; Winner, Beate

doi:10.1016/j.expneurol.2020.113466

Cited by 29 publications

(19 citation statements)

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“…For this, we made use of hiPSC-lines derived from a PD patient with a heterozygous SNCA Dupl , and compared the phenotypes in SNCA Dupl neural cells with those in hiPSC-derived cells from two healthy donors. To generate mDANs from hiPSC, we applied a small molecule-based protocol developed by Reinhardt et al [17] that is well established in our previous studies [13,18,19]. hiPSC differentiation involved the derivation of hiPSCs to the formation of embryoid bodies (EBs), the expansion and differentiation of NPCs, and the maturation of mDANs (Supplementary Figure S3A,B).…”

Section: Snca Duplication Leads To An Increased Asyn Protein Level In...mentioning

confidence: 99%

Interaction of Alpha Synuclein and Microtubule Organization Is Linked to Impaired Neuritic Integrity in Parkinson’s Patient-Derived Neuronal Cells

Seebauer

Schneider

Drobny

et al. 2022

IJMS

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Parkinson’s disease (PD) is neuropathologically characterized by the loss of dopaminergic neurons and the deposition of aggregated alpha synuclein (aSyn). Mounting evidence suggests that neuritic degeneration precedes neuronal loss in PD. A possible underlying mechanism could be the interference of aSyn with microtubule organization in the neuritic development, as implied by several studies using cell-free model systems. In this study, we investigate the impact of aSyn on microtubule organization in aSyn overexpressing H4 neuroglioma cells and midbrain dopaminergic neuronal cells (mDANs) generated from PD patient-derived human induced pluripotent stem cells (hiPSCs) carrying an aSyn gene duplication (SNCADupl). An unbiased mass spectrometric analysis reveals a preferential binding of aggregated aSyn conformers to a number of microtubule elements. We confirm the interaction of aSyn with beta tubulin III in H4 and hiPSC-derived mDAN cell model systems, and demonstrate a remarkable redistribution of tubulin isoforms from the soluble to insoluble fraction, accompanied by a significantly increased insoluble aSyn level. Concordantly, SNCADupl mDANs show impaired neuritic phenotypes characterized by perturbations in neurite initiation and outgrowth. In summary, our findings suggest a mechanistic pathway, through which aSyn aggregation interferes with microtubule organization and induces neurite impairments.

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Section: Snca Duplication Leads To An Increased Asyn Protein Level In...mentioning

confidence: 99%

Interaction of Alpha Synuclein and Microtubule Organization Is Linked to Impaired Neuritic Integrity in Parkinson’s Patient-Derived Neuronal Cells

Seebauer

Schneider

Drobny

et al. 2022

IJMS

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“…Additionally, the astrocytic SASP participates in driving pathological changes in the aging brain by generating a chronic inflammatory environment. Senescent astrocytes from humans and mice secrete inflammatory and proteolytic SASP factors, such as IL-6, IL-1β, CCL2, MMP-3, and MMP-9 [ 148 , 149 , 155 , 163 , 164 ]. Interestingly, these factors are elevated in the cerebrospinal fluid (CSF) and sera of AD patients, suggesting that senescence-associated inflammation accompanies and may contribute to the progression of AD [ 165 , 166 ].…”

Section: Mechanisms Of Astrocyte-mediated Neuropathology In the Aging...mentioning

confidence: 99%

Blood–Brain Barrier Dysfunction and Astrocyte Senescence as Reciprocal Drivers of Neuropathology in Aging

Preininger

Kaufer

2022

IJMS

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As the most abundant cell types in the brain, astrocytes form a tissue-wide signaling network that is responsible for maintaining brain homeostasis and regulating various brain activities. Here, we review some of the essential functions that astrocytes perform in supporting neurons, modulating the immune response, and regulating and maintaining the blood–brain barrier (BBB). Given their importance in brain health, it follows that astrocyte dysfunction has detrimental effects. Indeed, dysfunctional astrocytes are implicated in age-related neuropathology and participate in the onset and progression of neurodegenerative diseases. Here, we review two mechanisms by which astrocytes mediate neuropathology in the aging brain. First, age-associated blood–brain barrier dysfunction (BBBD) causes the hyperactivation of TGFβ signaling in astrocytes, which elicits a pro-inflammatory and epileptogenic phenotype. Over time, BBBD-associated astrocyte dysfunction results in hippocampal and cortical neural hyperexcitability and cognitive deficits. Second, senescent astrocytes accumulate in the brain with age and exhibit a decreased functional capacity and the secretion of senescent-associated secretory phenotype (SASP) factors, which contribute to neuroinflammation and neurotoxicity. Both BBBD and senescence progressively increase during aging and are associated with increased risk of neurodegenerative disease, but the relationship between the two has not yet been established. Thus, we discuss the potential relationship between BBBD, TGFβ hyperactivation, and senescence with respect to astrocytes in the context of aging and disease and identify future areas of investigation in the field.

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“…Senescence and reactivity are distinct astrocytic cell fates, yet they share some common features. A recent transcriptomic study revealed a wide range of senescent-related markers upregulated in senescent astrocytes such as SA-β-gal, IL6, IL8, IL1A, IL1B, CDKN1A , the p53/p21 WAF 1 and p16 INK 4 A /pRB pathways, CYR61 , CCND1 , IGFNP5 , and IGFBP2 ( Simmnacher et al, 2020 ). Senescent astrocytes also experience an upregulation of high-mobility group B (HMGB) proteins, increased production of vimentin and glial fibrillary acidic protein (GFAP), in addition to a reduced expression of neurotrophic factors and nuclear lamina protein laminB1 ( Han et al, 2020 ).…”

Section: Brain Cellular Senescence In Parkinson’s Diseasementioning

confidence: 99%

“…Some of the upregulated inflammatory marker genes are shared between reactive and senescent astrocytes. For example, astrocytes in both states experience upregulated pro-inflammatory cytokines, chemokines, proteases, and growth factors ( Maciel-Barón et al, 2016 ; Cohen and Torres, 2019 ; Simmnacher et al, 2020 ). The morphology of senescent astrocytes change to become flattened, enlarged, and have vacuolized lysosomes ( Bitto et al, 2010 ; Cohen and Torres, 2019 ).…”

Section: Brain Cellular Senescence In Parkinson’s Diseasementioning

confidence: 99%

“…The hiPSC derived astrocytes also had an increased number of 53BP1 foci due to the upregulation of DNA damage signaling, which stimulates SASP expression ( Chinta et al, 2018 ). Other environmentally toxic chemicals that have been linked to PD, like the pesticide rotenone and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), have also been shown to cause premature senescence in human astrocytes in a dose-dependent manner ( Wan et al, 2014 ; González-Barbosa et al, 2017 ; Simmnacher et al, 2020 ).…”

Section: Brain Cellular Senescence In Parkinson’s Diseasementioning

confidence: 99%

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Neuroglial Senescence, α-Synucleinopathy, and the Therapeutic Potential of Senolytics in Parkinson’s Disease

et al. 2022

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Parkinson’s disease (PD) is the most common movement disorder and the second most prevalent neurodegenerative disease after Alzheimer’s disease. Despite decades of research, there is still no cure for PD and the complicated intricacies of the pathology are still being worked out. Much of the research on PD has focused on neurons, since the disease is characterized by neurodegeneration. However, neuroglia has become recognized as key players in the health and disease of the central nervous system. This review provides a current perspective on the interactive roles that α-synuclein and neuroglial senescence have in PD. The self-amplifying and cyclical nature of oxidative stress, neuroinflammation, α-synucleinopathy, neuroglial senescence, neuroglial chronic activation and neurodegeneration will be discussed. Finally, the compelling role that senolytics could play as a therapeutic avenue for PD is explored and encouraged.

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Unique signatures of stress-induced senescent human astrocytes

Cited by 29 publications

References 100 publications

Interaction of Alpha Synuclein and Microtubule Organization Is Linked to Impaired Neuritic Integrity in Parkinson’s Patient-Derived Neuronal Cells

Interaction of Alpha Synuclein and Microtubule Organization Is Linked to Impaired Neuritic Integrity in Parkinson’s Patient-Derived Neuronal Cells

Blood–Brain Barrier Dysfunction and Astrocyte Senescence as Reciprocal Drivers of Neuropathology in Aging

Neuroglial Senescence, α-Synucleinopathy, and the Therapeutic Potential of Senolytics in Parkinson’s Disease

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