In a laboratory at Oregon Health & Science University, researchers have found that a rare variant of the APOE gene, first identified in New Zealand, kept two troublesome proteins from gathering in the brains of genetically prone mice. The discovery, reported in Cell Reports, adds Parkinson's and Lewy body dementia to a story that began with Alzheimer's, when a Colombian woman carrying the same mutation was spared the dementia her family line had been fated to suffer. It is a reminder that nature sometimes keeps quiet records of protection, waiting for patient observers to read them. Whether th
Rare APOE Christchurch Mutation Shields Mice From Parkinson's and Lewy Body Protein Buildup
In every case, the mice did not accumulate tau or alpha-synuclein.
Mark
What's actually new here? The Christchurch mutation has been in the news since 2019.
Mimi
Those earlier findings were about Alzheimer's and tau. This study shows the mutation also blocked alpha-synuclein, the protein tied to Parkinson's and Lewy body dementia.
Mark
So one gene variant touches two different diseases?
Mimi
In mice, yes. Both proteins failed to accumulate even though the animals were predisposed to it.
Luke
Keep the "in mice" attached. Nothing here shows the same thing in human Parkinson's patients.
Mark
Fair. What about the 2019 case?
Mimi
A woman from Colombia, destined for Alzheimer's, whose symptoms seemed delayed. That's the human thread, but it concerned Alzheimer's, not Parkinson's.
Luke
And "seemed to forestall" is careful wording. One case is suggestive, not proof.
Mark
What about the "super-APOE-2" description?
Mimi
That's Unni's characterization, and he limits it to this mouse model. APOE-2 gene therapies are already in development.
Luke
So the comparison is one researcher's reading of one animal study. Worth noting, not worth banking.
Mark
What comes next?
Mimi
Funding for more preclinical work, then persuading drug companies. Unni says testing would take several years.
Der Puls
- A gene variant nobody expected to matter may be quietly standing between brains and two of the most stubborn neurodegenerative diseases.
- The mice bred to accumulate alpha-synuclein and tau stayed clear of both proteins once the Christchurch mutation was added, a result that surprised the team.
- Researchers are racing to turn an animal finding into a hypothesis worthy of funding, with the lab now seeking grants to extend the work.
- Gene therapy built on this mutation, possibly even stronger than the APOE-2 version already under study, remains years away from human trials.
In a laboratory at Oregon Health & Science University, researchers have found that a rare variant of the APOE gene, first identified in New Zealand, kept two troublesome proteins from gathering in the brains of genetically prone mice. The discovery, reported in Cell Reports, adds Parkinson's and Lewy body dementia to a story that began with Alzheimer's, when a Colombian woman carrying the same mutation was spared the dementia her family line had been fated to suffer. It is a reminder that nature sometimes keeps quiet records of protection, waiting for patient observers to read them. Whether those mice foreshadow human relief remains an open question, one that will be answered slowly, by funding, by time, and by the long patience of medicine.
Researchers at Oregon Health & Science University have reported that a rare variant of the APOE gene, the Christchurch mutation, kept two disease-linked proteins from building up in the brains of mice engineered to accumulate them. The study, published this week in Cell Reports, suggests a link to Parkinson's disease that had not been shown before.
The mutation first surfaced in New Zealand and drew wide notice in 2019, when a woman from Colombia was found to carry it. Her family was genetically destined for Alzheimer's, yet the variant appeared to hold her dementia symptoms at bay. Earlier animal work had already shown it blocks the tau protein from clumping.
The OHSU team added the mutation to mice predisposed to build up both tau and alpha-synuclein, the protein central to Parkinson's and Lewy body dementia. Every mouse carrying the variant avoided accumulating either protein, extending the protection to a second, unrelated condition.
Vivek Unni, the senior author, said the finding hints at benefits no one had yet imagined. The work also sits beside existing gene therapies built on the more common APOE-2 variant. In this model, the Christchurch version looks even more protective, which Unni described as a kind of super-APOE-2.
The project was supported by OHSU's Alzheimer's and Parkinson's centers and by two nonprofits. The findings remain preclinical, and the lab is now seeking funding to continue, hoping to eventually persuade drug companies to test gene therapy in people. Unni estimates that path will take several years.
Researchers at Oregon Health & Science University have reported that a rare variant of the APOE gene, known as the Christchurch mutation, kept two disease-linked proteins from building up in the brains of mice that were bred to accumulate them. The study appeared this week in the journal Cell Reports, and it suggests a link between the mutation and Parkinson's disease that had not been shown before.
The mutation was first discovered in New Zealand. It drew wider attention in 2019, when a woman from Colombia was found to carry it. She belonged to a family genetically destined to develop Alzheimer's disease, yet the mutation seemed to forestall her dementia symptoms. Other work in animal models has since indicated that the variant prevents the Alzheimer's-related tau protein from aggregating in the brain.
The OHSU team worked with mouse models predisposed to accumulate both tau and alpha-synuclein, the protein that typifies the progression of Parkinson's disease and Lewy body dementia. The researchers added the Christchurch mutation to the mice's APOE gene and watched what happened. In every case, the mice with the mutation did not accumulate tau or alpha-synuclein, despite their predisposition. The result confirms the earlier tau findings and goes a step further by extending the protection to a second, unrelated protein.
Vivek Unni, M.D., Ph.D., the senior author and an associate professor of neurology at the OHSU School of Medicine, said the finding opens up the idea that the mutation could be helpful for many things researchers had not previously realized.
The work also sits alongside existing efforts. Gene therapies are already being developed around a more common version of the gene, APOE-2, which also appears to protect against Alzheimer's. Unni said that, at least in this mouse model, the Christchurch mutation appears even more protective, describing it as acting like a super-APOE-2. The study raises the possibility of gene-therapy approaches to forestall cognitive and motor impairments in Parkinson's and related conditions.
The project began when Unni and lead author Carlos Soto-Faguas, Ph.D., a postdoctoral researcher in his lab, received awards from OHSU's Oregon Alzheimer's Disease Research Center and Parkinson Center, and from the nonprofits American Parkinson Disease Association and Stop Alzheimer's Now. Co-authors are Abigail O'Niel, Elizabeth Saltonstall, Paul Mueller, Paula Sanchez-Molina, Lev Fedorov, Randall Woltjer and Jacob Raber.
The findings remain preclinical. Unni's lab is now seeking grant funding to extend the research, with the aim of eventually convincing drug companies to invest in clinical trials of APOE Christchurch gene therapy in people. He said it would take several years to test the idea.
Bemerkenswerte Zitate
The Christchurch mutation seems even more protective than APOE-2 and acts like a super-APOE-2, at least in the mouse model.— Vivek Unni, M.D., Ph.D., senior author, OHSU
It would take several years to test the idea.— Vivek Unni, M.D., Ph.D.
Möchten Sie die ganze Geschichte?
Das Original lesen bei News-Medical ↗