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α-synuclein suppresses microglial autophagy and promotes neurodegeneration in a mouse model of Parkinson's disease.

ABSTRACT: The cell-to-cell transfer of α-synuclein (α-Syn) greatly contributes to Parkinson's disease (PD) pathogenesis and underlies the spread of α-Syn pathology. During this process, extracellular α-Syn can activate microglia and neuroinflammation, which plays an important role in PD. However, the effect of extracellular α-Syn on microglia autophagy is poorly understood. In the present study, we reported that extracellular α-Syn inhibited the autophagy initiation, as indicated by LC3-II reduction and p62 protein elevation in BV2 and cultured primary microglia. The in vitro findings were verified in microglia-enriched population isolated from α-Syn-overexpressing mice induced by adeno-associated virus (AAV2/9)-encoded wildtype human α-Syn injection into the substantia nigra (SN). Mechanistically, α-Syn led to microglial autophagic impairment through activating toll-like receptor 4 (Tlr4) and its downstream p38 and Akt-mTOR signaling because Tlr4 knockout and inhibition of p38, Akt as well as mTOR prevented α-Syn-induced autophagy inhibition. Moreover, inhibition of Akt reversed the mTOR activation but failed to affect p38 phosphorylation triggered by α-Syn. Functionally, the in vivo evidence showed that lysozyme 2 Cre (Lyz2^cre )-mediated depletion of autophagy-related gene 5 (Atg5) in microglia aggravated the neuroinflammation and dopaminergic neuron losses in the SN and exacerbated the locomotor deficit in α-Syn-overexpressing mice. Taken together, the results suggest that extracellular α-Syn, via Tlr4-dependent p38 and Akt-mTOR signaling cascades, disrupts microglial autophagy activity which synergistically contributes to neuroinflammation and PD development.

SUBMITTER: Tu HY

PROVIDER: S-EPMC8672776 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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α-synuclein suppresses microglial autophagy and promotes neurodegeneration in a mouse model of Parkinson's disease.

Tu Hai-Yue HY Yuan Bao-Shi BS Hou Xiao-Ou XO Zhang Xiao-Jun XJ Pei Chong-Shuang CS Ma Ya-Ting YT Yang Ya-Ping YP Fan Yi Y Qin Zheng-Hong ZH Liu Chun-Feng CF Hu Li-Fang LF

Aging cell 20211122 12

The cell-to-cell transfer of α-synuclein (α-Syn) greatly contributes to Parkinson's disease (PD) pathogenesis and underlies the spread of α-Syn pathology. During this process, extracellular α-Syn can activate microglia and neuroinflammation, which plays an important role in PD. However, the effect of extracellular α-Syn on microglia autophagy is poorly understood. In the present study, we reported that extracellular α-Syn inhibited the autophagy initiation, as indicated by LC3-II reduction and p ...[more]

PMID: 34811872

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Project description:Parkinson's disease is characterized by a proteinopathy that includes aggregates of α-synuclein. A recent hypothesis proposes a prion-like spreading mechanism for this α-synucleinopathy. Early neuropathological deposits occur, among others, in the anterior olfactory nucleus (AON). This study investigates the anterograde and/or retrograde transmissibility of exogenous α-synuclein inoculated in the right AON of the A53T model of Parkinson's disease and wild-type mice as well as neuronal and glial involvement. Seven experimental groups were established: wild-type injected with tracers; A53T mice injected with either α-synuclein or saline 2 months beforehand; wild-type injected with either α-synuclein or saline 2 months beforehand; and wild-type injected with either α-synuclein or saline 4 months beforehand. Weight and behavioral changes were analyzed. Immunohistochemistry against α-synuclein, NeuN, Iba-1 and GFAP was performed. Volume and marker distributions in the olfactory bulb (OB), AON and piriform cortex were analyzed using unbiased stereology. The behavioral analyses reveal higher levels of hyperactivity in transgenic as compared to wild-type mice. Tract-tracing experiments show that the main contralateral afferent projections to the dorsal AON come from the AON and secondarily from the OB. In saline-injected transgenic animals, α-synuclein expression in the OB and the AON is higher in the left hemisphere than in the right hemisphere, which could be due to basal interhemispheric differences. α-synuclein injection could provoke a significant increase in the left hemisphere of the transgenic mice's OB, compared to saline-injected animals. Neuronal loss was observed in saline-injected transgenic mice relative to the saline-injected wild-type group. There were no overall differences in neuron number following injection of α-synuclein into either wild-type or transgenic mice, however some neuron loss was apparent in specific regions of α-synuclein injected wild-types. Microglia labeling appeared to be correlated with surgery-induced inflammation. Astroglial labeling was higher in transgenic animals, which could be due to endogenous α-synucleinopathy. This study suggests α-synucleinopathy induction, via retrograde and contralateral projections, within the olfactory system of transgenic animals.

Project description:BackgroundThe α-synuclein released by neurons activates microglia, which then engulfs α-synuclein for degradation via autophagy. Reactive microglia are a major pathological feature of Parkinson's disease (PD), although the exact role of microglia in the pathogenesis of PD remains unclear. Transient receptor potential vanilloid type 1 (TRPV1) channels are nonselective cation channel protein that have been proposed as neuroprotective targets in neurodegenerative diseases.MethodsUsing metabolic profiling, microglia energy metabolism was measured including oxidative phosphorylation and aerobic glycolysis. The mRFP-GFP-tagged LC3 reporter was introduced to characterize the role of TRPV1 in microglial autophagy. α-synuclein preformed fibril (PFF) TRPV1flox/flox; Cx3cr1Cre mouse model of sporadic PD were employed to study the capacity of TRPV1 activation to attenuate neurodegeneration process.ResultsWe found that acute exposure to PFF caused microglial activation as a result of metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis via the AKT-mTOR-HIF-1α pathway. Activated microglia eventually reached a state of chronic PFF-tolerance, accompanied by broad defects in energy metabolism. We showed that metabolic boosting by treatment with the TRPV1 agonist capsaicin rescued metabolic impairments in PFF-tolerant microglia and also defects in mitophagy caused by disruption of the AKT-mTOR-HIF-1α pathway. Capsaicin attenuated phosphorylation of α-synuclein in primary neurons by boosting phagocytosis in PFF-tolerant microglia in vitro. Finally, we found that behavioral deficits and loss of dopaminergic neurons were accelerated in the PFF TRPV1flox/flox; Cx3cr1Cre mouse model of sporadic PD. We identified defects in energy metabolism, mitophagy and phagocytosis of PFF in microglia from the substantia nigra pars compacta of TRPV1flox/flox; Cx3cr1Cre mice.ConclusionThe findings suggest that modulating microglial metabolism might be a new therapeutic strategy for PD.

Project description:Accumulation of neuronal α-synuclein is a prominent feature in Parkinson's disease. More recently, such abnormal protein aggregation has been reported to spread from cell to cell and exosomes are considered as important mediators. The focus of such research, however, has been primarily in neurons. Given the increasing recognition of the importance of non-cell autonomous-mediated neurotoxicity, it is critical to investigate the contribution of glia to α-synuclein aggregation and spread. Microglia are the primary phagocytes in the brain and have been well-documented as inducers of neuroinflammation. How and to what extent microglia and their exosomes impact α-synuclein pathology has not been well delineated. We report here that when treated with human α-synuclein preformed fibrils, exosomes containing α-synuclein released by microglia are fully capable of inducing protein aggregation in the recipient neurons. Additionally, when combined with microglial proinflammatory cytokines, these exosomes further increased protein aggregation in neurons. Inhibition of exosome synthesis in microglia reduced α-synuclein transmission. The in vivo significance of these exosomes was demonstrated by stereotaxic injection of exosomes isolated from α-synuclein preformed fibrils treated microglia into the mouse striatum. Phosphorylated α-synuclein was observed in multiple brain regions consistent with their neuronal connectivity. These animals also exhibited neurodegeneration in the nigrostriatal pathway in a time-dependent manner. Depleting microglia in vivo dramatically suppressed the transmission of α-synuclein after stereotaxic injection of preformed fibrils. Mechanistically, we report here that α-synuclein preformed fibrils impaired autophagy flux by upregulating PELI1, which in turn, resulted in degradation of LAMP2 in activated microglia. More importantly, by purifying microglia/macrophage derived exosomes in the CSF of Parkinson's disease patients, we confirmed the presence of α-synuclein oligomer in CD11b+ exosomes, which were able to induce α-synuclein aggregation in neurons, further supporting the translational aspect of this study. Taken together, our study supports the view that microglial exosomes contribute to the progression of α-synuclein pathology and therefore, they may serve as a promising therapeutic target for Parkinson's disease.

Dataset Information

α-synuclein suppresses microglial autophagy and promotes neurodegeneration in a mouse model of Parkinson's disease.

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α-synuclein suppresses microglial autophagy and promotes neurodegeneration in a mouse model of Parkinson's disease.

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