Study finds proof that immune defenses amplify Parkinson’s disease damage
UAB News -
The same mechanism that lets the immune system mount a massive attack against invading bacteria contributes to the destruction of brain cells as part of Parkinson’s disease, according to a study published online today in the Journal of Neuroscience.
Researchers from the University of Alabama at Birmingham (UAB) found that shutting down production of a key group of immune proteins, major histocompatibility complex II (MHCII), completely protected mice that displayed a “human version” of the disease from related nerve cell death.
The MHCII protein complex enables cells that first respond to infections to display pieces of bacteria or viruses on their surfaces for notice by a second part of the immune system. These displayed pieces of invaders trigger a massive, second wave of immune reactions led by T cells and B cells. While vital to body’s ability to combat infectious disease, full-scale immune responses cause disease-related inflammation and cell death when unleashed in the wrong place.
“We were surprised to find that blocking MHCII action rescued nerve cells from Parkinson’s disease mechanisms so quickly and completely,” said Ashley Harms, Ph.D, a postdoctoral scholar in the UAB Department of Neurology within the UAB School of Medicine, and lead author of the study. “The completeness of the rescue argues that this mechanism is at the heart of the immune-mediated aspect of Parkinson’s disease.”
The idea that the immune system plays a major role in Parkinson’s disease has been gaining momentum since September 2010, when a paper published by another group in Nature Genetics found that small changes in the gene for human leukocyte antigen, one piece of the MHCII complex, occurred much more often in patients with Parkinson’s disease.
Parkinson’s disease is the most common neurodegenerative movement disorder, with the steady loss of nerve cells eventually causing patients’ limbs to shake or become rigid. While much about its cause is still unknown, researchers agree than an early step in the disease is the build-up of a protein called alpha-synuclein in nerve cells, which causes them to self-destruct.
Once alpha-synuclein builds up, the question becomes whether immune cells in a given person’s brain will handle the buildup well or ramp up a misplaced, cell-killing immune response. The current study suggests that genes in microglia, the first-responder immune cells of the brain, are triggered to make many more MHCII complexes on their surfaces. This, in turn, enables more T cells to release chemicals called cytokines designed to kill bacteria, but that also destroy nearby human cells.
Conversely, mice genetically engineered to have alpha-synuclein build-up were protected against Parkinsonian nerve cell death when the current study authors shut down their gene coding for the MHCII complex in microglia.
Moving forward Harms and colleagues will seek to learn more about the relationship between MHCII and alpha-synuclein in hopes of informing drug design efforts. The team will, for instance, seek to learn whether it is a piece of alpha-synuclein, or of some related protein, which MHCII displays to trigger a larger immune reaction. They will also shut down the function of each protein in the MHCII complex to see which is most involved in the immune escalation.
“Alpha-synuclein may light the fire, but it appears that inflammation keeps it burning and may be responsible for the progression of Parkinson’s disease from year to year,” said David Standaert, M.D., Ph.D., chair of the UAB Department of Neurology and the study’s corresponding author.
He added that understanding the role of the immune system in Parkinson’s disease is a major research focus with the UAB Department of Neurology. Along with the work on the MHCII complex, another team is looking at whether interfering with an enzyme called leucine-rich repeat kinase 2 or LRRK2 can stop disease progression. LRRK2, like MCHII, is a critical player in the body’s immune response to alpha-synuclein buildup.
Along with Harms and Standaert, Shuwen Cao, Aaron Thome and Xinru Li in the UAB Center for Neurodegeneration and Experimental Therapeutics, Amber Rowse in the UAB Department of Microbiology, Leandra Mangieri and John Shacka in the UAB Department of Pathology, Chander Raman in the UAB Department of Medicine, and Randy Cron in the Division of Rheumatology, part of the Department of Pediatrics at Children’s Hospital of Alabama, made important contributions to the study. The work was supported by the RJG Foundation and the National Institutes of Health.