Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity

Bido, Simone; Muggeo, Sharon; Massimino, Luca; Marzi, Matteo Jacopo; Giannelli, Serena; Melacini, Elena; Nannoni, Melania; Gambarè, Diana; Bellini, Edoardo; Ordazzo, Gabriele; Rossi, G.; Maffezzini, Camilla; Iannelli, Angelo; Luoni, Mirko; Bagicaluppi, Marco; Gregori, Silvia; Nicassio, Francesco; Broccoli, Vania

doi:10.1038/s41467-021-26519-x

Cited by 101 publications

(80 citation statements)

References 58 publications

(61 reference statements)

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“…Liu et al, 2018; Moretti et al, 2017). aSyn pathology in our model therefore could be explained by an exhaustion of the autophagy machinery, as it was suggested recently (Bido et al, 2021), and the overall effect of inflammatory pathways on autophagy and aSyn pathology could be bimodal. Accordingly, degeneration of dopaminergic neurons and accumulation of aSyn aggregates was also observed in mice deficient for IFNβ (Ejlerskov et al, 2015; Magalhaes et al, 2021).…”

Section: Discussionsupporting

confidence: 61%

Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice

Szegő

Malz

Bernhardt

et al. 2022

Preprint

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The innate immune system can protect against certain aspects of neurodegenerative diseases, but also contribute to disease progression. Stimulator of interferon genes (STING) is activated after detection of cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part of the defense against viral pathogens, activating type I interferon and NF-kB/inflammasome signaling. In order to specifically test the relevance of this pathway for the degeneration of dopaminergic neurons in Parkinson's disease, we studied a mouse model with heterozygous expression of the constitutively active STING variant N153S. In adult mice expressing N153S STING, the number of dopaminergic neurons was smaller than in controls, as was the density of dopaminergic axon terminals and the concentration of dopamine in the striatum. We also observed alpha-synuclein pathology and a lower density of synaptic puncta. Neuroinflammation was quantified by staining astroglia and microglia, by measuring mRNAs, proteins and nuclear translocation of transcription factors. Neuroinflammatory markers were already elevated in juvenile mice, thus preceding the degeneration of dopaminergic neurons. Inflammation and neurodegeneration were blunted in mice deficient for signaling by type I interferons or inflammasomes, but not suppressed completely. Collectively, these findings demonstrate that chronic activation of the STING innate immunity pathway is sufficient to cause degeneration of dopaminergic neurons. This pathway could be targeted therapeutically.

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Section: Discussionsupporting

confidence: 61%

Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice

Szegő

Malz

Bernhardt

et al. 2022

Preprint

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“…Meantime, the removal of excessive ROS is also essential to the treatment of PD. [ 26 ] Therefore, by using 2,7‐dichlorofluorescin diacetate (DCFH‐DA) as ROS fluorescent probe, the ROS scavenging effect of different samples on the stimulated SH‐SY5Y cells was investigated by flow cytometry. [ 27 ] The ROS level increased a lot after stimulated treatment process compared with that in the blank group (Figure 3k,l).…”

Section: Resultsmentioning

confidence: 99%

Engineered Exosomes with Independent Module/Cascading Function for Therapy of Parkinson's Disease by Multistep Targeting and Multistage Intervention Method

Wang

Yang

et al. 2022

Advanced Materials

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process due to the aggressivity (e.g., electroporation or sonication methods), low yield, or poor controllability of traditional methods. [2,3] In addition, because the separation process from donor cells involves cumbersome processing steps, the weakened or lost function of exosomes in this process is difficult to be enhanced or compensated in the process of engineering. [4] In this work, the concept of "independent module/cascading function" is proposed for the controllable construction of engineered exosomes, that is, nanosized artificial module with specific functions is synthesized independently, and then selectively and controllably combined with natural exosome module in a "one-by-one" way to construct engineered exosome. The concept of "independent module" is not limited by the activity conditions of exosomes, so as to greatly enrich the preparation methods and types of artificial modules. Meantime, based on the selective and controllable combination technology between different modules, this method can effectively protect the integrity of exosome membrane structure and the activity of functional proteins and nucleic acids on membrane surface. "Cascading function" refers to endowing exosomes with new functions through rich design of artificial modules, and meeting the complex requirements of disease treatment through cascading effect, so as to play a remarkable therapeutic effect.In addition, this kind of engineered exosomes is applied to the treatment of Parkinson's disease (PD), aiming to solve the challenges of precise targeting and complex needs of PD treatment, of which the pathogenesis is complex and involves many factors and there is no effective method to completely cure it. [5] Up to now, the pathogenesis of PD can be summarized as the following process: nuclear gene mutation of dopaminergic neurons inhibits the normal hydrolysis of α-synuclein (α-syn) and promotes its aggregation in mitochondria, producing high concentration of reactive oxygen species (ROS), which further leads to enhanced expression of inducible nitric oxide synthase (iNOS) and neuroinflammation, and destroys itself and its surrounding neuronal cells. [6] Exosomes derived from stem cells have the potential to promote tissue repair and nerve regeneration, and have the ability to penetrate the blood-brain barrier Current exosome engineering methods usually lead to the damage of exosome morphology and membrane, which cannot meet the complex needs of disease treatment. Herein, the concept of an "independent module/cascading function" is proposed to construct an engineered exosome nanotherapy platform including an independent artificial module and a natural module. The artificial module with movement/chemotaxis function is first synthesized, and then it is controllably combined with the natural exosome module with "one by one" mode through a "differentiated" modification method. The whole process can not only maintain the activity of the natural exosome module, but also endows it with motion ability, so as to realize the purpose of...

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“…On the other hand, activated microglia release inflammatory cytokines, cause the aggregation of α-synuclein ( Gao et al, 2008 ), the accumulated α-synuclein makes dopamine neurons more sensitive to neuroinflammation, exacerbate dopaminergic neuron death and cause nerve damage in PD while also stimulating microglial activation and promoting a vicious cycle ( Block et al, 2007 ). Furthermore, some research shows that aggregation of α-synuclein in microglia induces dopaminergic neuron degeneration ( Bido et al, 2021 ). The above evidence shows that microglia play an important role in the pathological process of PD ( Rupprecht et al, 2010 ; Giga et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Translocator Protein Ligand Etifoxine Attenuates MPTP-Induced Neurotoxicity

Tian

Yang

et al. 2022

Front. Mol. Neurosci.

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Parkinson’s disease (PD) is a neurodegenerative disease, but the currently available treatments for this disease are symptomatic treatments. There is evidence that translocator protein (18 kDa) (TSPO) expression is upregulated in some neurodegenerative diseases, and TSPO ligands have obvious neuroprotective effects. However, the neuroprotective effects and other potential effects of the TSPO ligand etifoxine in PD remain unclear. Therefore, the present study was designed to explore the impacts of etifoxine on a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that etifoxine significantly reduced motor function deficits, decreased the loss of tyrosine hydroxylase-positive neurons in the substantia nigra, and attenuated the decrease in striatal dopamine levels in mice that received MPTP. Etifoxine diminished the production of inflammatory mediators and infiltration of leukocytes in the brain after MPTP exposure. In vitro studies suggested that microglia contribute to etifoxine’s neuroprotective effect. The results showed that etifoxine can alleviate MPTP-induced neurotoxicity and neuroinflammation, providing a new idea for the treatment of PD.

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Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity

Cited by 101 publications

References 58 publications

Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice

Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice

Engineered Exosomes with Independent Module/Cascading Function for Therapy of Parkinson's Disease by Multistep Targeting and Multistage Intervention Method

Translocator Protein Ligand Etifoxine Attenuates MPTP-Induced Neurotoxicity

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