Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson’s disease

Panicker, Nikhil; Kam, Tae In; Wang, Hu; Neifert, Stewart; Chou, Shih-Ching; Kumar, Manoj; Brahmachari, Saurav; Jhaldiyal, Aanishaa; Hinkle, Jared T.; Akkentli, Fatih; Mao, Xiaobo; Xu, Enquan; Karuppagounder, Senthilkumar S.; Hsu, Eric T.; Kang, Sung Ung; Pletniková, Olga; Troncoso, Juan C.; Dawson, Valina L.; Dawson, Ted M.

doi:10.1016/j.neuron.2022.05.009

Cited by 88 publications

(69 citation statements)

References 48 publications

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“…The inhibition of the hepatic Nlrp3 protects dopaminergic neurons by attenuating systemic inflammation in a MPTP/p mouse model of Parkinson’s disease [ 97 ]. Based on recent studies, the inflammasome spontaneously assembles in mice and human DA neurons when parkin function is lost, which causes DA neuron death and the symptoms of Parkinson’s disease in the animals [ 98 ].…”

Section: Roles Of Nlrp Inflammasome In Neuropsychiatric Disordersmentioning

confidence: 99%

The Significance of NLRP Inflammasome in Neuropsychiatric Disorders

et al. 2022

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The NLRP inflammasome is a multi-protein complex which mainly consists of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain. Its activation is linked to microglial-mediated neuroinflammation and partial neuronal degeneration. Many neuropsychiatric illnesses have increased inflammatory responses as both a primary cause and a defining feature. The NLRP inflammasome inhibition delays the progression and alleviates the deteriorating effects of neuroinflammation on several neuropsychiatric disorders. Evidence on the central effects of the NLRP inflammasome potentially provides the scientific base of a promising drug target for the treatment of neuropsychiatric disorders. This review elucidates the classification, composition, and functions of the NLRP inflammasomes. It also explores the underlying mechanisms of NLRP inflammasome activation and its divergent role in neuropsychiatric disorders, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, depression, drug use disorders, and anxiety. Furthermore, we explore the treatment potential of the NLRP inflammasome inhibitors against these disorders.

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Section: Roles Of Nlrp Inflammasome In Neuropsychiatric Disordersmentioning

confidence: 99%

The Significance of NLRP Inflammasome in Neuropsychiatric Disorders

et al. 2022

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“…Pyroptosis is a new form of programmed cell death characterized by its dependence on caspase-1, the NLRP3 inflammasome, and the release of a large number of inflammatory cytokines ( 20 ). Many studies have reported that pyroptosis plays an important role in PD, and inhibiting the activation of the NLRP3 inflammasomes can protect dopaminergic neurons ( 21 , 22 ). We have verified in vitro that BAG3 is involved in activation of the NLRP3 inflammasomes in BV2 cells induced by LPS, and to verify whether BAG3 plays this role in PD mice, we detected expression of NLRP3 and caspase-1 in the striatum of mice ( Figure 6A-6E ).…”

Section: Resultsmentioning

confidence: 99%

BAG3 promotes autophagy and suppresses NLRP3 inflammasome activation in Parkinson’s disease

Ying¹,

Lv²,

Yao³

et al. 2022

Ann Transl Med

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Background: Neuroinflammation mediated by microglia plays a key role in the pathogenesis of Parkinson's disease (PD), and our previous studies showed this was significantly inhibited by enhanced autophagy. In the autophagy pathway, Bcl2-associated athanogene (BAG)3 is a prominent co-chaperone, and we have shown BAG3 can regulate autophagy to clear the PD pathogenic protein α-synuclein. However, the connection between BAG3 and microglia mediated neuroinflammation is not clear.Methods: In this study, we explored whether BAG3 regulated related neuroinflammation and its original mechanism in PD. An inflammatory model of PD was established by injecting adeno-associated virus (AAV)-BAG3 into the bilateral striatum of C57BL/6 male mice to induce overexpression of BAG3, followed by injection of lipopolysaccharide (LPS). The striatum was extracted at 3 days after injection of LPS for Western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR), and immunohistochemical staining was performed at 21 days after injection. At the same time, LPS was used to induce activation of BV2 cells to verify the effect of BAG3 in vitro.Results: Overexpression of BAG3 reduced LPS-induced pyroptosis by reducing activation of caspase-1, the NOD-like receptor family, and the pyrin domain-containing 3 (NLRP3) inflammasome, and by release of interleukin (IL)-1β and tumor necrosis factor (TNF)-α. The LPS-induced inflammatory environment inhibits autophagy, and overexpression of BAG3 can restore autophagy, which may be the mechanism by which BAG3 reduces neuronal inflammation in PD.Conclusions: Our results demonstrate BAG3 promotes autophagy and suppresses NLRP3 inflammasome formation in PD.

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“…Loss of function mutation of Parkin leads to exacerbation of NLRP3 activation in blood-derived macrophages via induction of A20 ( Mouton-Liger et al, 2018 ). More recently, this E3 ubiquitin ligase Parkin is shown to negatively regulate NLRP3 in dopamine neurons via ubiquitinating NLRP3 for proteasomal degradation and reducing mitochondrial-derived ROS production ( Panicker et al, 2022 ).…”

Section: Inflammasome Activation In Parkinson’s Disease Pathogenesismentioning

confidence: 99%

Targeting the inflammasome in Parkinson’s disease

Goh

et al. 2022

Front. Aging Neurosci.

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Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in which neuroinflammation plays pivotal roles. An important mechanism of neuroinflammation is the NLRP3 inflammasome activation that has been implicated in PD pathogenesis. In this perspective, we will discuss the relationship of some key PD-associated proteins including α-synuclein and Parkin and their contribution to inflammasome activation. We will also review promising inhibitors of NLRP3 inflammasome pathway that have potential as novel PD therapeutics. Finally, we will provide a summary of current and potential in vitro and in vivo models that are available for therapeutic discovery and development.

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Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson’s disease

Cited by 88 publications

References 48 publications

The Significance of NLRP Inflammasome in Neuropsychiatric Disorders

The Significance of NLRP Inflammasome in Neuropsychiatric Disorders

BAG3 promotes autophagy and suppresses NLRP3 inflammasome activation in Parkinson’s disease

Targeting the inflammasome in Parkinson’s disease

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