Astrocytes Protect Human Dopaminergic Neurons from α-Synuclein Accumulation and Propagation

Tsunemi, Taiji; Ishiguro, Yuta; Yoroisaka, Asako; Valdez, Clarissa; Miyamoto, Kengo; Ishikawa, Keiichi; Saiki, Sachio; Akamatsu, Wado; Hattori, Nobutaka; Krainc, Dimitri

doi:10.1523/jneurosci.0954-20.2020

Cited by 77 publications

(70 citation statements)

References 49 publications

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“…This led to increased production of IL-1β and suggested that there is a direct link between the astrocyte lysosome and neuroinflammation in PD ( 71 ). Lysosomal degradation was also shown using human iPSC, from healthy controls or from patients carrying a mutation in lysosomal ATP13A2 , which were differentiated into midbrain dopamine neurons and astrocytes ( 72 ). This study showed that astrocytes rapidly internalised α-syn and when they were co-cultured with neurons, this led to a decreased accumulation of α-syn in neurons and as a consequence diminished interneuronal transfer of α-syn.…”

Section: Astrocytes and Their Role In Parkinson's Diseasementioning

confidence: 99%

“…This study showed that astrocytes rapidly internalised α-syn and when they were co-cultured with neurons, this led to a decreased accumulation of α-syn in neurons and as a consequence diminished interneuronal transfer of α-syn. Interestingly, loss of this protective function of astrocytes was seen with ATP13A2 deficiency, suggesting that this gene function in astrocytes, contributes partially to PD pathology ( 72 ).…”

Section: Astrocytes and Their Role In Parkinson's Diseasementioning

confidence: 99%

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The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

et al. 2021

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Parkinson's disease (PD), the second most common neurodegenerative disease, is characterised by the motor symptoms of bradykinesia, rigidity and resting tremor and non-motor symptoms of sleep disturbances, constipation, and depression. Pathological hallmarks include neuroinflammation, degeneration of dopaminergic neurons in the substantia nigra pars compacta, and accumulation of misfolded α-synuclein proteins as intra-cytoplasmic Lewy bodies and neurites. Microglia and astrocytes are essential to maintaining homeostasis within the central nervous system (CNS), including providing protection through the process of gliosis. However, dysregulation of glial cells results in disruption of homeostasis leading to a chronic pro-inflammatory, deleterious environment, implicated in numerous CNS diseases. Recent evidence has demonstrated a role for peripheral immune cells, in particular T lymphocytes in the pathogenesis of PD. These cells infiltrate the CNS, and accumulate in the substantia nigra, where they secrete pro-inflammatory cytokines, stimulate surrounding immune cells, and induce dopaminergic neuronal cell death. Indeed, a greater understanding of the integrated network of communication that exists between glial cells and peripheral immune cells may increase our understanding of disease pathogenesis and hence provide novel therapeutic approaches.

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Section: Astrocytes and Their Role In Parkinson's Diseasementioning

confidence: 99%

Section: Astrocytes and Their Role In Parkinson's Diseasementioning

confidence: 99%

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

et al. 2021

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“…Moreover, experiments with iPSC-derived astrocyte-neuron co-cultures revealed that astrocytes rapidly internalize neuronal a-SYN. By contrast, this intercellular transfer was prohibited in cultures from PD patients with mutations in the lysosomal storage protein ATP13A2 (135). This data not only suggests that astrocytes contribute to the neuronal a-SYN pathology in genetic PD, but that they may also act as mediators in neuroinflammatory processes.…”

Section: Astrocytes and Mitochondria In Inflammationmentioning

confidence: 80%

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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“…However, the effects of pathogenic α-synuclein species on astrocytes have not been thoroughly studied. Previous work has shown that astrocytes can protect dopaminergic neurons from α-synuclein deposition and degeneration (54). However, α-synuclein aggregates are also frequently observed in PD patients, where they disturb vital homeostatic functions and thereby exacerbate disease pathology in neurons (55).…”

Section: Discussionmentioning

confidence: 99%

Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB

Chou¹,

Chang²,

Krishnagiri³

et al. 2020

Preprint

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Parkinson’s disease (PD) is a neurodegenerative disorder characterized by death of midbrain dopamine neurons. The pathogenesis of PD is poorly understood, though misfolded and/or aggregated forms of the protein α-synuclein have been implicated in several neurodegenerative disease processes, including neuroinflammation and astrocyte activation. Astrocytes in the midbrain play complex roles during PD, initiating both harmful and protective processes that vary over the course of disease. However, despite their significant regulatory roles during neurodegeneration, the cellular and molecular mechanisms that promote pathogenic astrocyte activity remain mysterious. Here, we show that α-synuclein preformed fibrils (PFFs) induce pathogenic activation of human midbrain astrocytes, marked by inflammatory transcriptional responses, downregulation of phagocytic function, and conferral of neurotoxic activity. These effects required the necroptotic kinases RIPK1 and RIPK3, but were independent of MLKL and necroptosis. Instead, both transcriptional and functional markers of astrocyte activation occurred via RIPK-dependent activation of NF-κB signaling. Our study identifies a previously unknown function for α-synuclein in promoting neurotoxic astrocyte activation, as well as new cell death-independent roles for RIP kinase signaling in the regulation of glial cell biology and neuroinflammation. Together, these findings highlight previously unappreciated molecular mechanisms of pathologic astrocyte activation and neuronal cell death with implications for Parkinsonian neurodegeneration.

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Astrocytes Protect Human Dopaminergic Neurons from α-Synuclein Accumulation and Propagation

Cited by 77 publications

References 49 publications

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

Astrocyte-Neuron Metabolic Crosstalk in Neurodegeneration: A Mitochondrial Perspective

Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB

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