A rare genetic mutation may protect against developing Parkinson's disease and Lewy body dementia, a new study from researchers at Oregon Health & Science University suggests.
The study, published this week in the journal Cell Reports, for the first time suggests a link to Parkinson's involving the so-called Christchurch mutation of the APOE gene. The study raises the possibility of gene-therapy approaches to forestall cognitive and motor impairments in Parkinson's and related conditions.
Previous research — starting with the 2019 case of a woman from Colombia who carried the rare mutation first discovered in New Zealand — found that the mutation seems to forestall symptoms of dementia in people who are otherwise genetically destined to develop Alzheimer's disease.
OHSU researchers working in a rodent model have now discovered a link to Parkinson's.
"It opens up this idea that this Christchurch mutation could be helpful for a lot of things we didn't realize before," said senior author Vivek Unni, M.D., Ph.D., associate professor of neurology in the OHSU School of Medicine.
Other studies in animal models have shown the Christchurch mutation prevents the aggregation of the Alzheimer's-related tau protein from accumulating in the brain.
The OHSU study published this week confirms the same process in tau, while also going a step further and showing that the Christchurch mutation also prevents the accumulation of a different type of protein, known as alpha-synuclein, that typifies the progression of Parkinson's and Lewy Body dementia.
OHSU scientists used mouse models that are predisposed to accumulate alpha-synuclein and tau proteins in the brain.
Then, they added the Christchurch mutation to the APOE gene to see what would happen.
In each case, mice with the Christchurch mutation did not accumulate tau or alpha-synuclein proteins in the brain, despite their predisposition. In effect, the mutation seemed to protect the brain from the accumulation of proteins believed to drive both Alzheimer's and Parkinson's diseases.
Already gene therapies are being developed to leverage another more common version of the APOE gene (APOE-2) that also seems to be protective against Alzheimer's.
Unni said the Christchurch mutation seems to be even more protective than APOE-2 and "acts like a super-APOE-2," at least in the mouse model examined in the new study. His lab is seeking grant funding to extend preclinical research, with an eye toward eventually moving it far enough to convince drug companies to invest in APOE Christchurch gene therapy clinical trials with people.
"It would take several years to test the idea," he said.
The research began when Unni and lead author Carlos Soto-Faguas, Ph.D., a postdoctoral researcher in Unni's lab, received awards from OHSU's Oregon Alzheimer's Disease Research Center and Parkinson Center, and from the nonprofit organizations the American Parkinson Disease Association and Stop Alzheimer's Now.
In addition to Unni and Soto-Faguas, co-authors include Abigail O'Niel, Elizabeth Saltonstall, Paul Mueller, Ph.D., Paula Sanchez-Molina, Ph.D., Lev Fedorov, Ph.D., Randall Woltjer, M.D., Ph.D., and Jacob Raber, Ph.D.
The research was supported by funding from Stop Alzheimer's Now; the American Parkinson Disease Association postdoctoral research fellowship, award 1308711; a pilot grant with the OHSU Parkinson's Center, award 10255055; and the National Institute on Aging of the National Institutes of Health under award P30AG066518.
All research involving animal subjects at OHSU must be reviewed and approved by the university's Institutional Animal Care and Use Committee (IACUC). The IACUC's priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. No live animal work may be conducted at OHSU without IACUC approval.
