Research ArticleParkinson’s Disease

Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice

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Science Translational Medicine  31 Oct 2018:
Vol. 10, Issue 465, eaah4066
DOI: 10.1126/scitranslmed.aah4066

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Systemic inflammasome inhibitor for Parkinson’s disease

Brain accumulation of misfolded α-synuclein, progressive loss of dopaminergic neurons, and neuroinflammation are major hallmarks of Parkinson’s disease (PD). Although neuroinflammation has been shown to contribute to the pathophysiology of the disease, the mechanisms mediating the activation of inflammatory signals remain unclear. Gordon and colleagues now show that, in mouse models of PD, α-synuclein aggregates promote inflammasome activation in brain microglia. Oral treatment with an inflammasome inhibitor improved motor performance and reduced neuroinflammation, neurodegeneration, and α-synuclein accumulation in mouse models of α-synuclein–mediated toxicity. The results suggest that systemic delivery of inflammasome inhibitors might have therapeutic effects in PD.

Abstract

Parkinson’s disease (PD) is characterized by a profound loss of dopaminergic neurons in the substantia nigra, accompanied by chronic neuroinflammation, mitochondrial dysfunction, and widespread accumulation of α-synuclein–rich protein aggregates in the form of Lewy bodies. However, the mechanisms linking α-synuclein pathology and dopaminergic neuronal death to chronic microglial neuroinflammation have not been completely elucidated. We show that activation of the microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome is a common pathway triggered by both fibrillar α-synuclein and dopaminergic degeneration in the absence of α-synuclein aggregates. Cleaved caspase-1 and the inflammasome adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) were elevated in the substantia nigra of the brains of patients with PD and in multiple preclinical PD models. NLRP3 activation by fibrillar α-synuclein in mouse microglia resulted in a delayed but robust activation of the NLRP3 inflammasome leading to extracellular interleukin-1β and ASC release in the absence of pyroptosis. Nanomolar doses of a small-molecule NLRP3 inhibitor, MCC950, abolished fibrillar α-synuclein–mediated inflammasome activation in mouse microglial cells and extracellular ASC release. Furthermore, oral administration of MCC950 in multiple rodent PD models inhibited inflammasome activation and effectively mitigated motor deficits, nigrostriatal dopaminergic degeneration, and accumulation of α-synuclein aggregates. These findings suggest that microglial NLRP3 may be a sustained source of neuroinflammation that could drive progressive dopaminergic neuropathology and highlight NLRP3 as a potential target for disease-modifying treatments for PD.

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