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BRCA1 is already familiar to medical science and much of the general public as a gene whose mutation greatly heightens the risk of breast and ovarian cancer, given a high profile by the prophylactic mastectomies and oophorectomies of celebrities like Angelina Jolie.
Recent research, however, suggests another side to the BRCA1 protein—as a key player in brain functions underlying learning and memory.
Depletion of BRCA1, which repairs damaged DNA, may be a step on the pathway to Alzheimer’s disease, and possibly other neurodegenerative conditions as well, the research suggests.
These revelations are part of a broadening picture of brain function that highlights DNA breakage and repair as an essential event, rather than a costly error.
In a 2013 Nature Neuroscience paper, a team of researchers at the Gladstone Institute of Neurological Disease, an affiliate of University of California, San Francisco, reported a surprising discovery. When they examined brain cells of mice that had been put in a novel environment, they found increased double strand breaks (DSBs) in the mouse DNA, particularly in the dentate gyrus of the hippocampus, an area vital to learning and memory.
What made the discovery so striking is that DNA damage has been considered a bad thing. DSBs are especially dangerous, in that repair can easily introduce changes in genomic structure. In particular, there is a robust literature linking DNA damage to neurodegeneration.
“When we submitted this paper, calling attention to the fact that even normal brain activity induces such damage in nerve cells, reviewers wrote, ‘If this were true, it would be shocking’,” says senior author Lennart Mucke, distinguished professor of neuroscience at UCSF and a member of the Dana Alliance for Brain Initiatives.
Karl Herrup, professor and head of the division of life science at the Hong Kong University of Science and Technology, elaborates that view: “It seems such a reckless thing for a neuron to do, to put its genome at risk with every thought. Data is data, and you have to work with it, but the bigger picture is a very tough one to get your head around. Something is happening, but what it is, I don’t know.”
His reservations notwithstanding, in a “News and Views” commentary in the same journal where the paper appeared, Herrup called the implications of the research “far reaching; indeed, they have the potential to change our entire understanding of how genes are regulated in the nervous system.”
Research from MIT reported in Cell in 2015 complements the observations from Mucke’s lab and suggests a mechanism linking DNA breaks to brain function. Using cells cultured from mouse brains, researchers led by Li-Huei Tsai, director of the Picower Institute for Learning and Memory and also a member of the Dana Alliance, found that stimulation produced abundant DSBs, concentrated in the promoter region of early response genes.
These genes, Tsai explains, express transcription factors that initiate a cascade of molecular events vital for neuroplasticity—the changes in neuron circuitry underlying learning and memory.
Such early response genes are normally tightly wrapped. DSBs, the researchers showed, allow them to uncoil and activate. With these DNA breaks, “nature came up with a way of rapidly turning on gene expression,” Tsai suggests.
This model of normal neuron behavior only becomes feasible if the DSBs are promptly and correctly repaired. Tsai’s research showed just that: Within two hours, the number of DSBs returned to baseline. Breaks in DNA constantly occur, her work suggests, and are constantly mopped up.
The Gladstone Institute research found the same thing in live mice. A day after their exposure to a novel environment had increased DSBs, efficient DNA repair processes had apparently patched them up.
This process, however, appears vulnerable to the pathological changes that underlie Alzheimer’s disease. In the 2013 paper, the researchers showed that more DSBs occurred in mice genetically modified to accumulate the amyloid-beta protein characteristic of Alzheimer’s—and that many such breaks remained unrepaired.
“While in the normal mice DSBs returned to baseline after a day of rest, in the AD model mouse they didn’t,” says Gladstone researcher Elsa Suberbielle, first author of the paper. “It made us think that the problem was in the resolution of the breaks.”
BRCA1 to the rescue
Here’s where BRCA1 comes in. In subsequent research, reported in Nature Communications in 2015, the same research team looked at a number of compounds central to DNA repair. “To our surprise, the only factor that was drastically reduced—by more than 50 percent—in the AD-model mice was BRCA1,” Suberbielle says.
Cell culture experiments confirmed that BRCA1 depletion was apparently a consequence of amyloid beta accumulation.
When the researchers genetically manipulated the mice to knock down BRCA1 expression by half, they again found increased DSBs. The genetically modified mice also displayed neuronal damage and learning and memory deficits.
Human brains told a similar story. Comparing post-mortem biopsies from people with Alzheimer’s to those who had died cognitively intact, the researchers found that BRCA1 was 65–75 percent lower in the hippocampus—a key memory area and among the first to be damaged by AD—among the patients.
In people with mild cognitive impairment, a condition that carries increased risk of AD, BRCA1 was also reduced, albeit to a lesser extent. “It looks like BRCA1 depletion is a phenomenon occurring earlier in the disease [than severe impairment],” Suberbielle says.
Another experiment reported in the paper provided evidence for BRCA1’s role in normal brain physiology: Simply placing mice in the novel environment increased the protein substantially. “When neurons are activated, it really cranks up expression of BRCA1, as if anticipating DNA breaks that would need to be repaired,” Mucke says.
Her research should not give BRCA1 mutation carriers cause for alarm, Suberbielle says. “There’s a big difference between a BRCA1 deficit acquired late in life, through amyloid beta, and an inborn mutation; and no studies that indicate carriers of BRCA1 mutations are more likely to get AD.”
In some ways, the new findings fit a well-established paradigm, says Tsai. “They’re very consistent with something I’ve been pursuing: that defective DNA repair may be a very early step in the course of neurodegeneration, and that our cells have to maintain a very robust level of DNA repair because lesions are constantly generated.”
A far back as 2008, Tsai published papers suggesting that DSBs occurred in mouse models of neurodegenerative disease well before symptoms appeared. “So my feeling is, if we can enhance repair and protect the genome early on, we can protect cells from neurodegeneration.”
Karl Herrup observes that “DNA damage and repair has been for decades a hugely active area, but primarily populated by cancer biologists and immunologists. I’d love to see more CNS researchers get involved,” he says.
An important next step is determining whether elevating BRCA1 output can overcome AD pathology, says Suberbielle. “We have a new model mouse, expressing an artificially high level of BRCA1 in the brain, and we will test if this will counteract cognitive decline in the AD mice,” she says.
Such a demonstration would have profound implications, Tsai says. “DNA repair complexes are enormous. There are dozens of enzymes and scaffolding platforms involved, and we don’t know if BRCA1 is just one of many factors that need to be there. If BRCA1 overexpression can rescue [cognitive decline], that would say it plays a unique, important role.”
In that case, “the idea of using pharmacology to increase levels of expression of BRCA1 would be worth exploring,” Suberbielle says.
But much work stands between such research and clinical applications.
“Alzheimer’s is, for my money, far and away the most complex disease to confront the human nervous system, and the idea there’s a single pathway to regulate it is on the surface implausible,” Herrup says. He puts DNA damage and repair “high on the list of things to look at.”
Lennart Mucke plans to explore the relation of BRCA1 depletion to other aspects of AD pathology, such as tau protein and ApoE4, and to determine if similar depletions occur in other neurodegenerative disorders in which DNA damage is prominent, like ALS and Huntington’s disease.
“The bottom line is, whenever you open a door, there’s a lot more work to be done inside,” he says.