The researchers found that reducing BRCA1 (in red) in mouse brains and in cultured brain cells led to deficits associated with dementia.
Image credit: Lennart Mucke/UCSF
The researchers, from the nonprofit Gladstone Institutes in San Francisco, CA, and the University of California-San Francisco (UCSF), report their findings in the journal Nature Communications.
Senior author Lennart Mucke, a professor of neuroscience with roles in both organizations, says:
“It’s extremely interesting that one molecule can be critically involved in two apparently opposing conditions: cancer, in which too many cells are born and neurodegenerative disease, in which too many brain cells die off.”
The discovery of the BRCA1 gene over 20 years ago was a turning point in cancer research. It led to a blood test to look for inherited mutations linked to breast and ovarian cancers. According to the most recent estimates, among women who inherit a harmful BRCA1 mutation, 55-65% will develop breast cancer and 39% will develop ovarian cancer by the age of 70.
BRCA1 is a tumor suppressor gene that plays an important role in DNA repair. Inside cells, DNA exists as a double helix comprising two strands, like a twisted ladder. Now and again, breaks occur in the DNA strands, which are normally fixed by repair proteins like BRCA1. Broken strands that are not repaired normally trigger cell suicide.
There is a view that defects in DNA repair may contribute to brain disorders like Alzheimer’s – a disease that causes death of brain cells and is also characterized by build-up of faulty amyloid proteins in and around brain cells. However, it is not clear whether these proteins cause the brain cells to die or whether they are a byproduct of some other cause of the disease.
Amyloid clumps reduce BRCA1 and DNA repair, causing cell loss
In their study, the researchers found reduced levels of BRCA1 protein – but not other DNA repair proteins – in the brains of patients who had died with Alzheimer’s disease and also in the brains of mice bred to develop a form of Alzheimer’s.
Also, when they knocked out the BRCA1 gene in parts of the brains of healthy mice, it led to increased breaks in DNA and various neurological impairments.
And in another part of the study, the team found that reducing brain levels of BRCA1 in healthy mice caused them to develop problems with learning and memory.
Further investigation with mouse models of Alzheimer’s revealed even greater problems with learning and memory following reductions in BRCA1.
The researchers also found that adding amyloid protein precursor molecules to brain cells growing in culture reduced levels of BRCA1.
The team suggests that the accumulation of the faulty amyloid protein in the brain lowers levels of BRCA1 protein, which results in increased DNA damage in brain cells, and this in turn leads to dementia.
It falls to further studies to find out if BRCA1 could be a target for drugs to treat dementia, and whether the BRCA1 mutations that raise cancer risk may also affect the brain. Meanwhile, Prof. Mucke concludes:
“The functions of BRCA1 in the brain remain to be fully elucidated, but our findings suggest that it may play an important role in supporting critical brain functions in both health and disease.”
The study follows earlier research published in 2014 from which Medical News Today learned of a link between brain development and BRCA1.
Written by Catharine Paddock PhD