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DNA Repair Protein BRCA1 Implicated in Cognitive Function and Dementia

2015-11-30
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       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.

    The researchers began to look at a variety of DNA repair proteins within neurons since AD and other neurodegenerative disorders are typically associated with excessive DNA damage. Moreover, the investigators surmised that defective DNA repair was mediating the abnormal accumulation of DNA double-strand breaks (DSBs) in the neurons of transgenic mice containing the human amyloid precursor protein (hAPP). Yet, the discovery of BRCA1 involvement was an interesting and shocking discovery.

 

    “BRCA1 has so far been studied primarily in dividing (multiplying) cells and in cancer, which is characterized by abnormal increases in cell numbers,” explained lead author Elsa Suberbielle, Ph.D., 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.”

 

    The findings from this study were published online today in Nature Communications through an article entitled “DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice.”

 

    Typically, BRCA1 assists in the repair of DSBs, which often occur during cell injury, though until the current study the DNA repair protein hasn’t been shown to play much of a role in DSB repair within neuronal tissue. 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.

 

    In order to test their hypothesis, the Gladstone scientists reduced the levels of BRCA1 in mouse neurons and observed a marked accumulation of DNA damage and neuronal shrinkage—in addition to learning and memory deficits. Since this scenario in mice mimicked what is often seen in AD patients and tissues, the researchers decided to analyze BRCA1 levels in post-mortem AD brain samples and hAPP mice.

 

    “We found reduced levels of BRCA1, but not of other DNA repair factors, in the brains of AD patients and hAPP transgenic mice,” stated the authors.

 

    When compared to nondemented controls, the level of BRCA1 in AD tissue was decreased by 65-75%. Moreover, the scientists were able to show that treating neuronal cells in culture, caused a depletion of BRCA1—suggesting an important role in the aberrant DNA repair often seen in AD brains.

 

    The investigators are now testing whether increasing BRCA1 levels in hAPP mouse models can prevent or reverse neurodegeneration and memory problems, as this could open new pathways for drug intervention for AD patients.

 

    “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 people at risk for the disease,” noted senior author Lennart Mucke, M.D., 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.”

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