A gene called breast cancer factor 1, better known in biotech circles as BRCA1, is an important protein involved in DNA repair. For the public, it came under the spotlight when high-profile celebrities announced they were having preventive surgery due to certain mutations of the cancer promoting gene. Now researchers are finding that even a modest reduction of BRCA1 in the brain may be linked to the neurodegenerative Alzheimer's disease.
NIH-funded scientists at the University of California and the Gladstone Institute published their work this week in Nature Communications.
The group led by first author Elsa Suberbielle showed that lower levels of BRCA1 cause neurological problems by experimentally reducing BRCA1 in the neurons of mice. The results demonstrated that mice had learning and memory deficits as a consequence of lower BRCA1 expression.
"BRCA1 has so far been studied primarily in dividing (multiplying) cells and in cancer, which is characterized by abnormal increases in cell numbers," says Suberbielle. "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 causal link for BRCA1 and learning and memory is ascribed to the gene's ability to repair damaged DNA; the researchers hypothesize that this imbalance between damage and repair in the brain can bring about Alzheimer's-like cognitive problems.
They went a step further, showing that BRCA1 was reduced by 65% to 75% in the postmortem sections of brain tissue, derived from human Alzheimer's patients. By taking this clinical significance then back into the lab, they treated neuronal cells with amyloid-beta proteins which are known to accumulate in the brains of Alzheimer's patients. They also did this experiment in mice and what they found in both cases was that experimentally increasing this protein drives down the levels of BRCA1.
Lennart Mucke, who is a senior author of the study, said: "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. 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."
The growing evidence for faulty DNA repair in Alzheimer's disease will be added to soon--as the researchers plan to increase the levels of BRCA1 in a mouse model of the disease with hope that its progression will be prevented or reversed.