In a small laboratory in Oregon, researchers have found that a rare inherited variant of the APOE gene, first noticed in a family line in New Zealand's Christchurch and later in a Colombian woman who seemed spared from the dementia her genes foretold, appears to keep damaging proteins from gathering in the brains of mice. The protein at the center of Parkinson's and Lewy body dementia, alpha-synuclein, joins tau, the protein tied to Alzheimer's, as a suspect that the mutation seems able to hold at bay. For now this is a promising glimpse in animals, not a remedy for people, but it hints that a
Rare 'Christchurch' APOE Mutation Shields Mice From Parkinson's-Linked Protein Buildup
It "acts like a super-APOE-2," at least in the mouse model
Mark
So what's actually new here? The Christchurch mutation was already known.
Mimi
It was known for Alzheimer's. The 2019 case of the Colombian woman showed it seemed to delay dementia in someone genetically fated to get it. This is the first link to Parkinson's and Lewy body dementia.
Mark
And how did they test it?
Mimi
They used mice predisposed to accumulate alpha-synuclein and tau, then added the Christchurch mutation to the APOE gene. The mice with it didn't accumulate either protein.
Luke
Let me slow us down. This is mice. The source gives no sample sizes, and nobody has tested this in a person for Parkinson's.
Mimi
Fair. The lab itself frames it as preclinical, and Unni says testing the idea would take several years.
Mark
Unni called it a "super-APOE-2." What does that mean?
Mimi
APOE-2 is a common variant that also seems protective against Alzheimer's, and gene therapies are already being built around it. He thinks Christchurch is even more protective.
Luke
But he said that at least in this mouse model. It's a comparison within one study, not a proven human advantage.
Mark
Does preventing the protein buildup mean preventing the disease?
Luke
The source says the proteins are believed to drive these diseases. Believed is doing work there. The study shows prevention of accumulation, not prevention of symptoms.
Mimi
Right, and what comes next is more preclinical work to interest drug companies in human trials.
Il Polso
- A rare gene variant has stopped two harmful brain proteins from building up in mice that were bred to accumulate them.
- The finding is the first to link the Christchurch APOE mutation to Parkinson's and Lewy body dementia, widening a story that began with Alzheimer's.
- Researchers at OHSU are racing to build enough preclinical evidence to convince drug companies to fund human trials.
- The results remain confined to animals, and any human gene therapy is still years away from reaching patients.
In a small laboratory in Oregon, researchers have found that a rare inherited variant of the APOE gene, first noticed in a family line in New Zealand's Christchurch and later in a Colombian woman who seemed spared from the dementia her genes foretold, appears to keep damaging proteins from gathering in the brains of mice. The protein at the center of Parkinson's and Lewy body dementia, alpha-synuclein, joins tau, the protein tied to Alzheimer's, as a suspect that the mutation seems able to hold at bay. For now this is a promising glimpse in animals, not a remedy for people, but it hints that a single genetic quirk may one day reveal a shared path through several of the brain's most feared illnesses.
Researchers at Oregon Health & Science University have reported that a rare variant of the APOE gene, the Christchurch mutation, kept two damaging proteins from building up in the brains of mice. The work, published in Cell Reports, is the first to connect the mutation to Parkinson's disease and Lewy body dementia.
The mutation takes its name from New Zealand, where it was first found. It drew wide attention in 2019 when a woman from Colombia was discovered to carry it. She belonged to a family genetically destined for Alzheimer's, yet the mutation seemed to hold back her symptoms. Animal studies since then have suggested it blocks the buildup of tau, the protein linked to Alzheimer's.
The OHSU team asked whether that protection reached further. They bred mice predisposed to accumulate either alpha-synuclein, the protein that defines Parkinson's and Lewy body dementia, or tau, then added the Christchurch mutation. In every case the mutated mice did not accumulate either protein. The tau result confirmed earlier work; the alpha-synuclein result is new.
Senior author Vivek Unni described the mutation as potentially useful for many conditions not previously recognized. In his mouse model it appears even more protective than the more common APOE-2 variant, which is already the target of gene therapy efforts. Still, nothing has been tested in people. Unni's lab hopes its preclinical work will persuade drug companies to fund human trials, a process that would 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 damaging proteins from building up in the brains of mice. The finding, published in the journal Cell Reports, is the first to tie the mutation to Parkinson's disease and to Lewy body dementia.
The mutation takes its name from New Zealand, where it was first discovered. It drew wide attention in 2019, when a woman from Colombia was found to carry it. She belonged to a group of people otherwise genetically destined to develop Alzheimer's disease, yet the mutation appeared to hold back her dementia symptoms. Work in animal models since then has indicated that it prevents aggregation of tau, the protein associated with Alzheimer's.
The OHSU team set out to see whether the protection extended further. They used mouse models bred to be predisposed to accumulating either alpha-synuclein or tau in the brain. Alpha-synuclein is the protein that typifies the progression of Parkinson's and Lewy body dementia. The researchers then added the Christchurch mutation to the mice's APOE gene and watched what happened.
In every case, the mice carrying the mutation did not accumulate tau or alpha-synuclein, despite their built-in predisposition. The tau result confirmed what earlier animal studies had shown. The alpha-synuclein result is the new part. Both proteins are believed to drive the diseases in question, so the mutation seemed to shield the brain from the buildup behind both Alzheimer's and 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.
The work arrives while gene therapies are already under development around another, far more common version of the gene, APOE-2, which also appears protective against Alzheimer's. Unni said that, at least in the mouse model used in this study, the Christchurch mutation looks even more protective than APOE-2. He described it as acting like a "super-APOE-2." The study raises the possibility that a gene therapy could one day forestall both the cognitive and motor impairments seen in Parkinson's and related conditions.
The results are still preclinical, and nothing has yet been tested in people. Unni's lab hopes to extend its preclinical research far enough to persuade drug companies to invest in clinical trials of an APOE Christchurch gene therapy in humans. Even then, he said, it would take several years to test the idea. The next thing to watch is whether further animal work holds up and attracts that industry backing.
Citazioni salienti
It opens up this idea that this Christchurch mutation could be helpful for a lot of things we didn't realize before.— Vivek Unni, M.D., Ph.D., senior author, OHSU School of Medicine
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