DNA recombination identified in brain cells, linked to Alzheimer’s.


The neurons of the human brain are widely assumed to be encoded within a constant genome, with set genetic variant products and functions for neuronal networks.  Somatic gene recombination, which change germline DNA sequences to increase molecular diversity, have been documented in non-neuronal cells in the body, however, this has never been seen in the brain.  Now, a study from researchers at Sanford Burnham identifies gene recombination in neurons which produce thousands of new gene variants within Alzheimer’s disease brains. The team state their data reveals for the first time how the Alzheimer’s-linked gene, amyloid precursor protein (APP), is recombined using the same type of enzyme found in HIV.  The study is published in the journal Nature.

Previous studies show scientists discovered certain cells could shuffle and edit DNA, known as somatic recombination, where some immune cells snip out sections of genes that code for proteins to detect or fight pathogens and splice the remaining pieces together to create new varieties. The body’s B cells, for example, can potentially spawn about 1 quadrillion types of antibodies, enough to fend off an enormous range of bacteria, viruses, and other foreign bodies. The current study analyzes neurons from the donated brains of six healthy elderly people and seven patients who had the non-inherited form of Alzheimer’s disease, to find conclusive evidence of somatic recombination in the brain.

The current study tests whether the cells in these brains harbor different versions of the gene for APP, the source of the plaques in the brains of people with Alzheimer’s disease.  Results show that the neurons in the Alzheimer’s disease brains carry thousands of variants of the APP gene. Data findings show that the process requires reverse transcription and insertion of the variants back into the original genome, producing permanent DNA sequence changes within the cell’s DNA blueprint.

Results show that the gene recombination process requires an enzyme called reverse transcriptase, the same type of enzyme HIV uses to infect cells. The lab stress that although there is no medical evidence that HIV or AIDS causes Alzheimer’s disease, existing FDA-approved antiretroviral therapies for HIV, which block reverse transcriptase, could be used to halt the recombination process and could be explored as a new treatment for Alzheimer’s disease. The group go on to add that the relative absence of proven Alzheimer’s disease in the aging HIV population on antiretroviral medication, supports this hypothesis.

The team surmise that their findings identify gene recombination in neurons in the brain, which were found to be both a normal process for the brain and one which goes wrong in Alzheimer’s disease.  For the future, the researchers state that other groups need to replicate their work to confirm their findings, and add, if somatic recombination occurs in neurons, it could also be involved in other brain diseases, such as Parkinson’s disease.

Source: Sanford Burnham Prebys Medical Discovery Institute (SBP)

 

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