Alpha-synuclein/MPP+ mediated activation of NLRP3 inflammasome through microtubule-driven mitochondrial perinuclear transport

Yang, Xueping; Ma, Han; Yv, Qingyun; Ye, Fanlong; He, Zhong; Chen, Sheng; Keram, Alimu; Li, Wen-Wei; Zhu, Min

doi:10.1016/j.bbrc.2022.01.047

Cited by 9 publications

(3 citation statements)

References 39 publications

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“…MTPT is less toxic in vivo and is converted to 1-methyl-1-4-phenylpyridinium (MPP+) to cause dopaminergic neuronal degeneration and death [ 56 , 57 ]. MPP+ inhibits the mitochondrial respiration in dopaminergic neurons by suppressing the complex I of the electron transport chain, which results in ATP depletion and increased reactive oxidative species (ROS) [ 58 , 59 ]. MPP+ activates WWOX via Y33 phosphorylation in the rat brain to induce neuronal death [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

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Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration

Lin

Shih

Yap

et al. 2022

IJMS

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When WWOX is downregulated in middle age, aggregation of a protein cascade, including TRAPPC6AΔ (TPC6AΔ), TIAF1, and SH3GLB2, may start to occur, and the event lasts more than 30 years, which results in amyloid precursor protein (APP) degradation, amyloid beta (Aβ) generation, and neurodegeneration, as shown in Alzheimer’s disease (AD). Here, by treating neuroblastoma SK-N-SH cells with neurotoxin MPP+, upregulation and aggregation of TPC6AΔ, along with aggregation of TIAF1, SH3GLB2, Aβ, and tau, occurred. MPP+ is an inducer of Parkinson’s disease (PD), suggesting that TPC6AΔ is a common initiator for AD and PD pathogenesis. Zfra, a 31-amino-acid zinc finger-like WWOX-binding protein, is known to restore memory deficits in 9-month-old triple-transgenic (3xTg) mice by blocking the aggregation of TPC6AΔ, SH3GLB2, tau, and amyloid β, as well as inflammatory NF-κB activation. The Zfra4-10 peptide exerted a strong potency in preventing memory loss during the aging of 3-month-old 3xTg mice up to 9 months, as determined by a novel object recognition task (ORT) and Morris water maize analysis. Compared to age-matched wild type mice, 11-month-old Wwox heterozygous mice exhibited memory loss, and this correlates with pT12-WWOX aggregation in the cortex. Together, aggregation of pT12-WWOX may link to TPC6AΔ aggregation for AD progression, with TPC6AΔ aggregation being a common initiator for AD and PD progression.

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Section: Discussionmentioning

confidence: 99%

“…Conceivably, the pY33WW peptide blocks the function of the endogenous full-length pY33-WWOX in the rat brain. pY33-WWOX becomes proapoptotic when it is overexpressed [ 59 , 60 , 61 , 62 ].…”

Section: Discussionmentioning

confidence: 99%

Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration

Lin

Shih

Yap

et al. 2022

IJMS

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“…Beyond the causes of inflammasome activation already mentioned, mitochondrial dysfunction may also partly explain the activation mechanism of the inflammasome [ 97 ]. The altered mitochondrial function, structure, and changes in mitochondrial membrane potential can increase inflammasome activity through microtubules [ 97 , 98 ]. Considering this as a potential therapeutic target, MCC950 is currently a promising therapy.…”

Section: Inflammasomementioning

confidence: 99%

Neuroinflammation and Parkinson’s Disease—From Neurodegeneration to Therapeutic Opportunities

Araújo

Caridade-Silva

Macedo

et al. 2022

Cells

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Clinically, it is characterized by a progressive degeneration of dopaminergic neurons (DAn), resulting in severe motor complications. Preclinical and clinical studies have indicated that neuroinflammation can play a role in PD pathophysiology, being associated with its onset and progression. Nevertheless, several key points concerning the neuroinflammatory process in PD remain to be answered. Bearing this in mind, in the present review, we cover the impact of neuroinflammation on PD by exploring the role of inflammatory cells (i.e., microglia and astrocytes) and the interconnections between the brain and the peripheral system. Furthermore, we discuss both the innate and adaptive immune responses regarding PD pathology and explore the gut–brain axis communication and its influence on the progression of the disease.

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Downregulation of Fidgetin-Like 2 Increases Microglial Function: The Relationship Between Microtubules, Morphology, and Activity

Smith,

Gregor,

Baker

et al. 2024

Mol Neurobiol

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The microtubule cytoskeleton regulates microglial morphology, motility, and effector functions. The microtubule-severing enzyme, fidgetin-like 2 (FL2), negatively regulates cell motility and nerve regeneration, making it a promising therapeutic target for central nervous system injury. Microglia perform important functions in response to inflammation and injury, but how FL2 affects microglia is unclear. In this study, we investigated the role of FL2 in microglial morphology and injury responses in vitro. We first determined that the pro-inflammatory stimulus, lipopolysaccharide (LPS), induced a dose- and time-dependent reduction in FL2 expression associated with reduced microglial ramification. We then administered nanoparticle-encapuslated FL2 siRNA to knockdown FL2 and assess microglial functions compared to negative control siRNA and vehicle controls. Time-lapse live-cell microscopy showed that FL2 knockdown increased the velocity of microglial motility. After incubation with fluorescently labeled IgG-opsonized beads, FL2 knockdown increased phagocytosis. Microglia were exposed to low-dose LPS after nanoparticle treatment to model injury-induced cytokine secretion. FL2 knockdown enhanced LPS-induced cytokine secretion of IL-1α, IL-1β, and TNFα. These results identify FL2 as a regulator of microglial morphology and suggest that FL2 can be targeted to increase or accelerate microglial injury responses. Graphical Abstract

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Alpha-synuclein/MPP+ mediated activation of NLRP3 inflammasome through microtubule-driven mitochondrial perinuclear transport

Cited by 9 publications

References 39 publications

Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration

Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration

Neuroinflammation and Parkinson’s Disease—From Neurodegeneration to Therapeutic Opportunities

Downregulation of Fidgetin-Like 2 Increases Microglial Function: The Relationship Between Microtubules, Morphology, and Activity

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