Chronic inflammation is a hallmark of many diseases, including neurodegenerative diseases. As evidence grows that inflammation in the brain contributes to the development and progression of Parkinson's, The Michael J. Fox Foundation (MJFF) is prioritizing research into exactly how inflammation affects the brain and how we might treat it. An article published last week in Nature Biotechnology looks at some of these efforts, including one of our priority targets.
Inflammation is more complicated than "good" or "bad." It has important immune system functions, such as fighting off infection. But when inflammation becomes chronic, it can also damage brain cells. In Parkinson's, evidence suggests that chronic inflammation appears early and continues throughout the disease course.
Strategies to treat this by targeting microglia — the brain's main immune cells — often lead to unfortunate side effects because they hamper both chronic inflammation and beneficial immune system functions. However, another immune system target, called inflammasomes, may be the key to reducing harmful brain inflammation without interfering with critical immune functions.
Inflammasomes are multi-protein complexes that initiate inflammatory responses. In the brain one specific inflammasome, NLRP3 is involved in perpetuating chronic inflammation and damaging (and sometimes killing) brain cells.
In Nature, my MJFF colleague Kuldip Dave, director of research programs, explains: "We're slowly building the target validity for NLRP3." The Michael J. Fox Foundation began funding research into this target in 2015 and has now invested over $1.5 million. One program, at Dartmouth University, showed increases in NLRP3 and other inflammasome proteins in the brains of Parkinson's patients. With additional MJFF funding, this team is assessing whether NLRP3 activation is present in all Parkinson's patients or just a subset, and whether it changes during the disease.
In 2015, we also funded a team at the University of Queensland in Australia. These researchers discovered that certain stressors common in the brains of people with Parkinson's (e.g., oxidative stress, mitochondrial dysfunction, alpha-synuclein) can activate NLRP3. They also tested a small molecule that reduced NLRP3 activation and protected brain cells. A third MJFF-supported group at the Institute for the Brain and Spinal Cord in France demonstrated increased NLRP3 activation in cells affected by PRKN, a gene that is mutated in some familial forms of Parkinson's.
Thanks to MJFF-funded research, drugs targeting NLRP3 are now in development for Parkinson's. One team we supported has founded a biotech, Inflazome, to develop a Parkinson's therapy. We expect to continue our funding for research in inflammation in Parkinson's disease. During his interview with Nature, Kuldip Dave said that drugs targeting NLRP3 have enough evidence to move toward human testing, stating, "This is ready."