Role of α-synuclein in microglia: autophagy and phagocytosis balance neuroinflammation in Parkinson’s disease

Lv, Qiankun; Tao, Kang-Xin; Wang, Xiaobo; Yao, Xiao-Yu; Pang, Meng-Zhu; Liu, Junyi; Wang, Fen; Liu, Chunfeng

doi:10.1007/s00011-022-01676-x

Cited by 36 publications

(23 citation statements)

References 235 publications

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“…This effect was initially restricted to the activation induced by α-Syn in fibrillar form [ 175 ] but the recent results by Scheiblich et al (2021) [ 163 ] extended the capacity to activate microglial inflammasome at the α-SynOs. The inflammasome activation by α-SynOs in microglial cells has been associated with inhibition of an autophagic mechanism and increased TNF-α release [ 176 , 177 , 178 ]. The activation of autophagy, on the other hand, affects the accumulation of α-Syn [ 179 ] overexpression of the Bcl2-associated athanogene (BAG)3 promoted autophagy and reduced the activation of the NLRP3 inflammasome induced by LPS regulating autophagy [ 180 ].…”

Section: Alpha-synuclein and Inflammationmentioning

confidence: 99%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

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Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson’s disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.

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Section: Alpha-synuclein and Inflammationmentioning

confidence: 99%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

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“…Additionally, properly functioning microglia can phagocytose and degrade both Aβ and α-Syn. It is only when microglia lose the ability to degrade misfolded proteins and the load of Aβ or α-Syn becomes too high that aggregation and progression of disease state occurs in AD and PD, respectively. − Recent research supports chronic inflammation and NLRP3 inflammasome stimulation decreases microglial autophagy, leading to increased Aβ or α-Syn production and aggregation in the brain. − Furthermore, inflammation in other glial cells, namely astrocytes, leaves them unable to properly perform metabolic, structural, homeostatic, and neuroprotective tasks . Our study revealed that downregulation of NF-κB and NLRP3 decreases astrocyte inflammation in addition to microglial inflammation.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 72%

“…Based on the extensive evidence supporting the central involvement of NLRP3 inflammasome formation following NF-κB activation in the progression of neurodegenerative diseases, it is important to develop potential therapeutics to inhibit NF-κB and NLRP3. Therapeutic intervention to target and inhibit NLRP3 inflammasome formation arises as a potential three-hit treatment against neurodegenerative diseases by (1) reducing inflammatory signaling among microglia and astrocytes, − (2) preventing propagation of misfolded proteins, − and (3) upregulating microglia autophagy to accelerate removal of misfolded proteins. − No studies to date have explored combined NF-κB and NLRP3 inhibition as a therapeutic intervention for neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

“…Active caspase-1 cleaves pro-IL-1β and pro-IL-18 into their mature and biologically active forms, cytokines IL-1β and IL-18. , In mouse models of APP/PS1 mutation and a tauopathy, NLRP3 inflammasome assembly has been identified as a significant contributor to inflammatory-related amplification of Aβ plaques and neurofibrillary tangles. , Similarly, the NLRP3 inflammasome promotes α-Syn production in mouse models of PD. , Activation of NF-kB in prion disease augments neuronal death by increasing the expression of pro-apoptotic genes and triggering the release of cytochrome C, resulting in mitochondrial dysfunction and endoplasmic reticulum stress . Additionally, the upregulation of inflammatory cytokines IL-1β and tumor necrosis factor (TNF), formerly known as tumor necrosis factor α (TNFα), at sites of synaptic damage triggers the production of reactive oxygen species including hydrogen peroxide and nitric oxide, leading to excitotoxicity and neuronal death. − Beyond induction of inflammation and propagation of misfolded proteins, it has been proposed that activation of the NLRP3 inflammasome during neurodegenerative diseases inhibits microglial autophagy, dampening the identification and degradation of misfolded protein aggregates in AD, PD, and prion disease. − …”

Section: Introductionmentioning

confidence: 99%

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Targeting Neuroinflammation by Pharmacologic Downregulation of Inflammatory Pathways Is Neuroprotective in Protein Misfolding Disorders

Risen,

Boland,

Sharma

et al. 2024

ACS Chem. Neurosci.

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Neuroinflammation plays a crucial role in the development of neurodegenerative protein misfolding disorders. This category of progressive diseases includes, but is not limited to, Alzheimer's disease, Parkinson's disease, and prion diseases. Shared pathogenesis involves the accumulation of misfolded proteins, chronic neuroinflammation, and synaptic dysfunction, ultimately leading to irreversible neuronal loss, measurable cognitive deficits, and death. Presently, there are few to no effective treatments to halt the advancement of neurodegenerative diseases. We hypothesized that directly targeting neuroinflammation by downregulating the transcription factor, NF-κB, and the inflammasome protein, NLRP3, would be neuroprotective. To achieve this, we used a cocktail of RNA targeting therapeutics (SB_NI_112) shown to be brain-penetrant, nontoxic, and effective inhibitors of both NF-κB and NLRP3. We utilized a mouse-adapted prion strain as a model for neurodegenerative diseases to assess the aggregation of misfolded proteins, glial inflammation, neuronal loss, cognitive deficits, and lifespan. Prion-diseased mice were treated either intraperitoneally or intranasally with SB_NI_112. Behavioral and cognitive deficits were significantly protected by this combination of NF-κB and NLRP3 downregulators. Treatment reduced glial inflammation, protected against neuronal loss, prevented spongiotic change, rescued cognitive deficits, and significantly lengthened the lifespan of prion-diseased mice. We have identified a nontoxic, systemic pharmacologic that downregulates NF-κB and NLRP3, prevents neuronal death, and slows the progression of neurodegenerative diseases. Though mouse models do not always predict human patient success and the study was limited due to sample size and number of dosing methods utilized, these findings serve as a proof of principle for continued translation of the therapeutic SB_NI_112 for prion disease and other neurodegenerative diseases. Based on the success in a murine prion model, we will continue testing SB_NI_112 in a variety of neurodegenerative disease models, including Alzheimer's disease and Parkinson's disease.

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“…As PD progresses, through the PET assay, an early inflammation in the brainstem before cortical spreading is detected. In the initial stages of PD, an elevated microglial activation appears to be widespread in the substantia nigra [ 78 ]. Although CHI3L1 is involved in synaptic degeneration, glial activation, inflammation, and AD co-pathology, its CSF levels do not differ significantly between PD patients and healthy controls [ 79 ].…”

Section: Chitinases Parkinson’s Disease (Pd) and Dementia With Lewy B...mentioning

confidence: 99%

Chitinase Signature in the Plasticity of Neurodegenerative Diseases

Russo

Valle

Casabona

et al. 2023

IJMS

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Several reports have pointed out that Chitinases are expressed and secreted by various cell types of central nervous system (CNS), including activated microglia and astrocytes. These cells play a key role in neuroinflammation and in the pathogenesis of many neurodegenerative disorders. Increased levels of Chitinases, in particular Chitotriosidase (CHIT-1) and chitinase-3-like protein 1 (CHI3L1), have been found increased in several neurodegenerative disorders. Although having important biological roles in inflammation, to date, the molecular mechanisms of Chitinase involvement in the pathogenesis of neurodegenerative disorders is not well-elucidated. Several studies showed that some Chitinases could be assumed as markers for diagnosis, prognosis, activity, and severity of a disease and therefore can be helpful in the choice of treatment. However, some studies showed controversial results. This review will discuss the potential of Chitinases in the pathogenesis of some neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, to understand their role as distinctive biomarkers of neuronal cell activity during neuroinflammatory processes. Knowledge of the role of Chitinases in neuronal cell activation could allow for the development of new methodologies for downregulating neuroinflammation and consequently for diminishing negative neurological disease outcomes.

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Role of α-synuclein in microglia: autophagy and phagocytosis balance neuroinflammation in Parkinson’s disease

Cited by 36 publications

References 235 publications

Alpha Synuclein: Neurodegeneration and Inflammation

Alpha Synuclein: Neurodegeneration and Inflammation

Targeting Neuroinflammation by Pharmacologic Downregulation of Inflammatory Pathways Is Neuroprotective in Protein Misfolding Disorders

Chitinase Signature in the Plasticity of Neurodegenerative Diseases

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