Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson’s disease: an in vivo11C-BU99008 PET study

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Abstract

Do astrocytes play a role in the initiation and progression of Parkinson’s disease? Wilson et al. reveal activation of astrocytes in early Parkinson’s disease, likely in response to the presence of abnormal proteins. Loss of astrocytes occurs upon disease progression, however, and correlates with increasing cognitive impairment.

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Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease

Angelique Di Domenico, Giulia Carola, Carles F Calatayud … (2019)

Summary Parkinson's disease (PD) is associated with the degeneration of ventral midbrain dopaminergic neurons (vmDAns) and the accumulation of toxic α-synuclein. A non-cell-autonomous contribution, in particular of astrocytes, during PD pathogenesis has been suggested by observational studies, but remains to be experimentally tested. Here, we generated induced pluripotent stem cell-derived astrocytes and neurons from familial mutant LRRK2 G2019S PD patients and healthy individuals. Upon co-culture on top of PD astrocytes, control vmDAns displayed morphological signs of neurodegeneration and abnormal, astrocyte-derived α-synuclein accumulation. Conversely, control astrocytes partially prevented the appearance of disease-related phenotypes in PD vmDAns. We additionally identified dysfunctional chaperone-mediated autophagy (CMA), impaired macroautophagy, and progressive α-synuclein accumulation in PD astrocytes. Finally, chemical enhancement of CMA protected PD astrocytes and vmDAns via the clearance of α-synuclein accumulation. Our findings unveil a crucial non-cell-autonomous contribution of astrocytes during PD pathogenesis, and open the path to exploring novel therapeutic strategies aimed at blocking the pathogenic cross talk between neurons and glial cells.

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Astrocytic expression of Parkinson's disease-related A53T α-synuclein causes neurodegeneration in mice

Xing-Long Gu, Cai-Xia Long, Lixin Sun … (2010)

Background Parkinson's disease (PD) is the most common movement disorder. While neuronal deposition of α-synuclein serves as a pathological hallmark of PD and Dementia with Lewy Bodies, α-synuclein-positive protein aggregates are also present in astrocytes. The pathological consequence of astrocytic accumulation of α-synuclein, however, is unclear. Results Here we show that PD-related A53T mutant α-synuclein, when selectively expressed in astrocytes, induced rapidly progressed paralysis in mice. Increasing accumulation of α-synuclein aggregates was found in presymptomatic and symptomatic mouse brains and correlated with the expansion of reactive astrogliosis. The normal function of astrocytes was compromised as evidenced by cerebral microhemorrhage and down-regulation of astrocytic glutamate transporters, which also led to increased inflammatory responses and microglial activation. Interestingly, the activation of microglia was mainly detected in the midbrain, brainstem and spinal cord, where a significant loss of dopaminergic and motor neurons was observed. Consistent with the activation of microglia, the expression level of cyclooxygenase 1 (COX-1) was significantly up-regulated in the brain of symptomatic mice and in cultured microglia treated with conditioned medium derived from astrocytes over-expressing A53T α-synuclein. Consequently, the suppression of COX-1 activities extended the survival of mutant mice, suggesting that excess inflammatory responses elicited by reactive astrocytes may contribute to the degeneration of neurons. Conclusions Our findings demonstrate a critical involvement of astrocytic α-synuclein in initiating the non-cell autonomous killing of neurons, suggesting the viability of reactive astrocytes and microglia as potential therapeutic targets for PD and other neurodegenerative diseases.

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Neuroinflammation mediated by IL-1β increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease

James Koprich, Casper Reske-Nielsen, Prabhakar Mithal … (2008)

Background The etiology of Parkinson's disease (PD) remains elusive despite identification of several genetic mutations. It is more likely that multiple factors converge to give rise to PD than any single cause. Here we report that inflammation can trigger degeneration of dopamine (DA) neurons in an animal model of Parkinson's disease. Methods We examined the effects of inflammation on the progressive 6-OHDA rat model of Parkinson's disease using immunohistochemistry, multiplex ELISA, and cell counting stereology. Results We show that a non-toxic dose of lipopolysaccharide (LPS) induced secretion of cytokines and predisposed DA neurons to be more vulnerable to a subsequent low dose of 6-hydroxydopamine. Alterations in cytokines, prominently an increase in interleukin-1beta (IL-1β), were identified as being potential mediators of this effect that was associated with activation of microglia. Administration of an interleukin-1 receptor antagonist resulted in significant reductions in tumor necrosis factor-α and interferon-γ and attenuated the augmented loss of DA neurons caused by the LPS-induced sensitization to dopaminergic degeneration. Conclusion These data provide insight into the etiology of PD and support a role for inflammation as a risk factor for the development of neurodegenerative disease.

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Journal

Title: Brain

Publisher: Oxford University Press (OUP)

ISSN (Print): 0006-8950

ISSN (Electronic): 1460-2156

Publication date Created: October 2019

Publication date Created: October 01 2019

Publication date Created: August 26 2019

Publication date Other: October 2019

Publication date (Print): October 01 2019

Publication date (Electronic): August 26 2019

Volume: 142

Issue: 10

Pages: 3116-3128

Affiliations

[1 ]Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

[2 ]Neuropsychopharmacology Unit, Centre for Academic Psychiatry, Division of Brain Sciences, Imperial College London, Burlington Danes Building, Hammersmith Hospital campus, 160 Du Cane Road, London, UK

[3 ]Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK

[4 ]Invicro LLC, Centre for Imaging Sciences, Hammersmith Hospital, London, UK

[5 ]Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

Article

DOI: 10.1093/brain/awz260

PubMed ID: 31504212

SO-VID: f3513dc3-4eab-45cd-b438-fc822e9b559b

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Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson’s disease: an in vivo11C-BU99008 PET study

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Most cited references 39

Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease

Astrocytic expression of Parkinson's disease-related A53T α-synuclein causes neurodegeneration in mice

Neuroinflammation mediated by IL-1β increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease

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