Inflammation-related Protein Complex a Potential Therapy Target for Parkinson’s, Study Says

Oral administration of a small molecule specifically blocked the activation of a stress-sensing protein complex called the NLRP3 inflammasome and prevented the loss of brain cells, resulting in significantly improved motor function in a mouse model of Parkinson’s disease, a study reports.

Findings also revealed that the inflammasome is activated in Parkinson’s patients.

“We have used this discovery to develop improved drug candidates and hope to carry out human clinical trials in 2020,” Trent Woodruff, PhD, the study’s senior author, said in a press release.

The study, “Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice,” appeared in the journal Science Translational Medicine.

Parkinson’s is characterized by the progressive loss of dopamine-producing neurons in an area of the brain called the substantia nigra, leading to the characteristic motor symptoms. Dysfunction of the mitochondria, which provide energy to cells, accumulation of protein clumps primarily containing fibrils of alpha-synuclein, and neuroinflammation are other well-known alterations occurring in the brains of Parkinson’s patients.

The inflammasome is a multiprotein complex responsible for the activation of inflammatory responses that works as a sensor of environmental and cellular stress. Work in Alzheimer’s disease has shown that the accumulation of protein clumps can activate inflammasomes, driving inflammation in the central nervous system (CNS), which consists of the brain and spinal cord.

Using postmortem brains from Parkinson’s patients and mouse models of the disease, researchers from The University of Queensland in Australia showed that both fibrils of alpha-synuclein and loss of dopamine-producing neurons triggered the activation of the NLRP3 inflammasome in microglia — a type of cell that plays a crucial role in the CNS during immune responses to infection or injury.

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“We found a key immune system target, called the NLRP3 inflammasome, lights up in Parkinson’s patients, with signals found in the brain and even in the blood,” said Woodruff, who is an associate professor in the faculty of medicine at Queensland.

An activated NLRP3 inflammasome was associated with the release of the pro-inflammatory molecule interleukin (IL)-1beta and ASC protein, which is also involved in the inflammatory response, in mouse cells, along with increased levels of activated caspase-1 — an enzyme responsible for the generation of active IL-1beta — in the substantia nigra of Parkinson’s patients.

The team found that low doses of MCC950, a small-molecule inhibitor of NLRP3, completely suppressed inflammasome activation in mouse microglia as well as ASC protein release. Importantly, once-daily, oral administration of MCC950 inhibited inflammasome activation, alpha-synuclein clumping, and loss of dopamine-producing neurons in a mouse model of Parkinson’s disease, while also easing their motor deficits.

“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 [Parkinson’s],” the researchers wrote in the study.

Targeting microglia would represent a different strategy to that currently used by pharmaceutical companies, which have attempted to treat neurodegenerative disorders by blocking neurotoxic proteins that accumulate in the brain, said Matthew A. Cooper, PhD, one of the study’s authors and a researcher at the UQ Institute for Molecular Bioscience.

He also said that overactivation of the immune system, as well as brain inflammation and damage caused by microglia, can occur in Parkinson’s and other age-related diseases. “MCC950 effectively ‘cooled the brains on fire’, turning down microglial inflammatory activity, and allowing neurons to function normally,” he said.

“The findings provide exciting new insight into how the spread of toxic proteins occurs in Parkinson’s disease and highlights the important role of the immune system in this process,” said Richard Gordon, PhD, the study’s first author and an advance Queensland research fellow.

Gordon added that the team is now exploring approaches such as repurposing medications to target processes implicated in inflammasome-mediated disease progression.

The study was funded by The Michael J. Fox Foundation for Parkinson’s Research and Shake it Up Australia Foundation.