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DNA repair protein BRCA1 implicated in cognitive function and dementia

Depletion of BRCA1, long known to cause cancer, impairs brain cell function and may contribute to cognitive decline in Alzheimer's disease

Date:
November 30, 2015
Source:
Gladstone Institutes
Summary:
Researchers have shown for the first time that the protein BRCA1 is required for normal learning and memory and is depleted by Alzheimer's disease. BRCA1 is a key protein involved in DNA repair, and mutations that impair its function increase the risk for breast and ovarian cancer. The new study demonstrates that Alzheimer's disease is associated with a depletion of BRCA1 in neurons and that BRCA1 depletion can cause cognitive deficits.
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Researchers from the Gladstone Institutes have shown for the first time that the protein BRCA1 is required for normal learning and memory and is depleted by Alzheimer's disease.

BRCA1 is a key protein involved in DNA repair, and mutations that impair its function increase the risk for breast and ovarian cancer. The new study, published in Nature Communications, demonstrates that Alzheimer's disease is associated with a depletion of BRCA1 in neurons and that BRCA1 depletion can cause cognitive deficits.

"BRCA1 has so far been studied primarily in dividing (multiplying) cells and in cancer, which is characterized by abnormal increases in cell numbers," says first author Elsa Suberbielle, PhD, a research scientist at the Gladstone Institutes. "We were therefore surprised to find that it also plays important roles in neurons, which don't divide, and in a neurodegenerative disorder that is characterized by a loss of these brain cells."

In dividing cells, BRCA1 helps repair a type of DNA damage known as double-strand breaks that can occur when cells are injured. In neurons, though, such breaks can occur even under normal circumstances, for example, after increased brain activity, as shown by the team of Gladstone scientists in an earlier study. The researchers speculated that in brain cells, cycles of DNA damage and repair facilitate learning and memory, whereas an imbalance between damage and repair disrupts these functions.

To test this idea, the scientists experimentally reduced BRCA1 levels in the neurons of mice. Reduction of the DNA repair factor led to an accumulation of DNA damage and to neuronal shrinkage. It also caused learning and memory deficits. Because Alzheimer's disease is associated with similar neuronal and cognitive problems, the scientists wondered whether the problems might be mediated by depletion of BRCA1. They therefore analyzed neuronal BRCA1 levels in post-mortem brains of Alzheimer's patients.

Compared with non-demented controls, neuronal BRCA1 levels in the patients were reduced by 65-75%. To determine the causes of this depletion, the investigators treated neurons grown in cell culture with amyloid-beta proteins, which accumulate in Alzheimer brains. These proteins depleted BRCA1 in the cultured neurons, suggesting that they may be an important cause of the faulty DNA repair seen in Alzheimer brains. Further supporting this conclusion, the researchers demonstrated that accumulation of amyloid-beta in the brains of mice also reduced neuronal BRCA1 levels. They are now testing whether increasing BRCA1 levels in these mouse models can prevent or reverse neurodegeneration and memory problems.

"Therapeutic manipulation of repair factors such as BRCA1 may ultimately be used to prevent neuronal damage and cognitive decline in patients with Alzheimer's disease or in people at risk for the disease," says senior author Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease. "By normalizing the levels or function of BRCA1, it may be possible to protect neurons from excessive DNA damage and prevent the many detrimental processes it can set in motion."


Story Source:

Materials provided by Gladstone Institutes. Note: Content may be edited for style and length.


Journal Reference:

  1. Elsa Suberbielle, Biljana Djukic, Mark Evans, Daniel H. Kim, Praveen Taneja, Xin Wang, Mariel Finucane, Joseph Knox, Kaitlyn Ho, Nino Devidze, Eliezer Masliah, Lennart Mucke. DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice. Nature Communications, 2015; 6: 8897 DOI: 10.1038/ncomms9897

Cite This Page:

Gladstone Institutes. "DNA repair protein BRCA1 implicated in cognitive function and dementia." ScienceDaily. ScienceDaily, 30 November 2015. <www.sciencedaily.com/releases/2015/11/151130084043.htm>.
Gladstone Institutes. (2015, November 30). DNA repair protein BRCA1 implicated in cognitive function and dementia. ScienceDaily. Retrieved March 28, 2024 from www.sciencedaily.com/releases/2015/11/151130084043.htm
Gladstone Institutes. "DNA repair protein BRCA1 implicated in cognitive function and dementia." ScienceDaily. www.sciencedaily.com/releases/2015/11/151130084043.htm (accessed March 28, 2024).

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