Cdk5-Dependent Activation of Neuronal Inflammasomes in Parkinson's Disease

Zhang, Pei; Shao, Xia; Qi, Guangjian; Chen, Qiang; Bu, Lu-Lu; Chen, Lijun; Shi, Jing; Ming, Jie; Tian, Bo

doi:10.1002/mds.26488

Cited by 93 publications

(68 citation statements)

References 45 publications

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“…Our studies have been consistent with these reports [14], however, we also unexpectedly identified NLRP3 expression in a subset of surviving DA neurons in late stage PD patients and neuronal cell models [40]. Others report inflammasome activity in neurons [27, [49][50][51], but to our knowledge no in vivo studies have examined directly the function of NLRP3 in DA neurons in the context of aging. In this study, we generated mice with the potential for DA neuron specific NLRP3 inflammasome hyperactivity and analyzed the animals throughout aging ( others who report suppression of NLRP3 inflammasome-driven inflammation dependent on the DRD1 dopamine receptor in bone marrow derived macrophages [67].…”

Section: Discussionsupporting

confidence: 92%

“…Evidence of NLRP3 inflammasome protein expression in neurons has been reported by our laboratory and others[27,40,[49][50][51], however the impact of neuronal inflammasome activity in aging animals has not been analyzed directly. Having identified NLRP3 expression in remaining DA neurons from PD patients and in human neuronal cell lines[40], we established a genetically engineered mouse model to characterize longitudinally the effect of enhanced DA neuron-specific NLRP3 inflammasome activity throughout aging.…”

mentioning

confidence: 98%

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Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

Herrmann

Anderson

Martinez

et al. 2020

Preprint

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Background An association between neuroinflammation and age-related neurologic disorders has been established but the molecular mechanisms and cell types involved have not been thoroughly characterized. Activity of the proinflammatory NLRP3 inflammasome is implicated in Alzheimer’s and Parkinson’s disease and our recent studies in patients suggest that dopaminergic neurons within the degenerating mesencephalon express NLRP3 throughout the progression of PD. Here, we directly test the impact of enhanced inflammasome activity in mesencephalic neurons by characterizing motor function, tissue integrity, and neuroinflammation in aging mice harboring hyper-activating mutations within the endogenous murine Nlrp3 locus, enabled only in cells expressing the dopamine neuron specific Slc6a3 promoter. Methods We compared mice harboring inducible alleles encoding the cryopyrin-associated periodic syndrome activating mutations Nlrp3A350V and Nlrp3L351P inserted into the endogenous mouse Nlrp3 locus. Tissue specific expression was driven by breeding these animals with mice expressing Cre recombinase under the control of the dopamine neuron specific Slc6a3 promoter. The experimental mice, designed to express hyperactive NLRP3 only when the endogenous mouse Nlrp3 promotor is active in dopaminergic neurons, were analyzed throughout 18 months of aging using longitudinal motor function assessments. Biochemical and histologic analyses of mesencephalic tissues were conducted in 1- and 18-month old animals. Results We observed progressive and significant deficits in motor function in animals expressing Nlrp3L351P, compared with animals expressing Nlrp3WT and Nlrp3A350V. Age-dependent neuroinflammatory changes in the mesencephalon were noted in all animals. Analysis of GFAP-immunoreactive astrocytes in the substantia nigra revealed a significant increase in astrocyte number in animals expressing Nlrp3L351P compared with Nlrp3WT and Nlrp3A350V. Further analysis of Nlrp3L351P striatal tissues indicated genotype specific gliosis, elevated Il1b expression, and both morphologic and gene expression indicators of proinflammatory A1 astrocytes. Conclusions Dopaminergic neurons have the potential to accumulate NLRP3 inflammasome activators with age, including reactive oxygen species, dopamine metabolites, and misfolded proteins. Results indicate the Nlrp3 locus is active in dopaminergic neurons in aging mice, and that the hyperactive Nlrp3L351P allele can drive neuroinflammatory changes in association with progressive behavioral deficits. Findings suggest neuronal NLRP3 inflammasome activity may contribute to neuroinflammation observed during normal aging and the progression of neurologic disorders.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 98%

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

Herrmann

Anderson

Martinez

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Evidence of NLRP3 inflammasome protein expression in neurons has been reported by our laboratory and others [27,40,[49][50][51], however the impact of neuronal inflammasome activity in aging animals has not been analyzed directly. Having identified NLRP3 expression in remaining DA neurons from PD patients and in human neuronal cell lines [40], we established a genetically engineered mouse model to characterize longitudinally the effect of enhanced DA neuron-specific NLRP3 inflammasome activity throughout aging.…”

Section: Resultsmentioning

confidence: 93%

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

Herrmann

Anderson

Martinez

et al. 2020

Preprint

View full text Add to dashboard Cite

Background : An association between neuroinflammation and age-related neurologic disorders has been established but the molecular mechanisms and cell types involved have not been thoroughly characterized. Activity of the proinflammatory NLRP3 inflammasome is implicated in Alzheimer’s and Parkinson’s disease and our recent studies in patients suggest that dopaminergic neurons within the degenerating mesencephalon express NLRP3 throughout the progression of PD. Here, we directly test the impact of enhanced inflammasome activity in mesencephalic neurons by characterizing motor function, tissue integrity, and neuroinflammation in aging mice harboring hyper-activating mutations within the endogenous murine Nlrp3 locus, enabled only in cells expressing the dopaminergic neuron specific Slc6a3 promoter. Methods: We compared mice harboring inducible alleles encoding the cryopyrin-associated periodic syndrome activating mutations Nlrp3A350V and Nlrp3L351P inserted into the endogenous mouse Nlrp3 locus. Tissue specific expression was driven by breeding these animals with mice expressing Cre recombinase under the control of the dopaminergic neuron specific Slc6a3 promoter. The experimental mice, designed to express hyperactive NLRP3 only when the endogenous mouse Nlrp3 promotor is active in dopaminergic neurons, were analyzed throughout 18 months of aging using longitudinal motor function assessments. Biochemical and histologic analyses of mesencephalic tissues were conducted in 1- and 18-month old animals.Results : We observed progressive and significant deficits in motor function in animals expressing Nlrp3L351P, compared with animals expressing Nlrp3WT and Nlrp3A350V. Age-dependent neuroinflammatory changes in the mesencephalon were noted in all animals. Analysis of GFAP-immunoreactive astrocytes in the substantia nigra revealed a significant increase in astrocyte number in animals expressing Nlrp3L351P compared with Nlrp3WT and Nlrp3A350V. Further analysis of Nlrp3L351P striatal tissues indicated genotype specific gliosis, elevated Il1b expression, and both morphologic and gene expression indicators of proinflammatory A1 astrocytes.Conclusions : Dopaminergic neurons have the potential to accumulate NLRP3 inflammasome activators with age, including reactive oxygen species, dopamine metabolites, and misfolded proteins. Results indicate the Nlrp3 locus is active in dopaminergic neurons in aging mice, and that the hyperactive Nlrp3L351P allele can drive neuroinflammatory changes in association with progressive behavioral deficits. Findings suggest neuronal NLRP3 inflammasome activity may contribute to neuroinflammation observed during normal aging and the progression of neurologic disorders.

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“…The neurotoxicity induced by α-synuclein is partially through the activation of CDK5, a key kinase of CNS required for regulating cellular events in neuronal diseases [125], which can effectively participate in controlling inflammasome activation and oxidative stress in PD progression as well [17,126]. Notably, the downregulation of miR-124 in SNpc dopamine neurons of a MPTP-intoxicated PD mouse model has been found to modulate the expression of calpain1/CDK5 pathway proteins [127].…”

Section: Mechanisms Of Mir-124 In Parkinson's Diseasementioning

confidence: 99%

The Potential Role of MicroRNA-124 in Cerebral Ischemia Injury

Liu

Feng

et al. 2019

IJMS

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Cerebral ischemia injury, the leading cause of morbidity and mortality worldwide, initiates sequential molecular and cellular pathologies that underlie ischemic encephalopathy (IE), such as ischemic stroke, Alzheimer disease (AD), Parkinson’s disease (PD), epilepsy, etc. Targeted therapeutic treatments are urgently needed to tackle the pathological processes implicated in these neurological diseases. Recently, accumulating studies demonstrate that microRNA-124 (miR-124), the most abundant miRNA in brain tissue, is aberrant in peripheral blood and brain vascular endothelial cells following cerebral ischemia. Importantly, miR-124 regulates a variety of pathophysiological processes that are involved in the pathogenesis of age-related IE. However, the role of miR-124 has not been systematically illustrated. Paradoxically, miR-124 exerts beneficial effects in the age-related IE via regulating autophagy, neuroinflammation, oxidative stress, neuronal excitability, neurodifferentiation, Aβ deposition, and hyperphosphorylation of tau protein, while it may play a dual role via regulating apoptosis and exerts detrimental effects on synaptic plasticity and axonal growth. In the present review, we thus focus on the paradoxical roles of miR-124 in age-related IE, as well as the underlying mechanisms. A great understanding of the effects of miR-124 on the hypoxic–ischemic brain will open new avenues for therapeutic approaches to protect against cerebral ischemia injury.

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Cdk5-Dependent Activation of Neuronal Inflammasomes in Parkinson's Disease

Abstract: Together, our results indicated that Cdk5-dependent activation of neuronal inflammasomes was involved in the progression of PD.

Cited by 93 publications

References 45 publications

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

The Potential Role of MicroRNA-124 in Cerebral Ischemia Injury

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