British Scientists Find a DNA Mechanism to Prevent ALS and Alzheimer’s

17/07/2017 - 2 minutes

Researchers at the University of Sheffield discovered a mechanism driving neuron death and reversed neurodegeneration in rodents and human cells.

A new study published in Nature Neuroscience describes a previously unknown mechanism behind the death of neurons in neurodegenerative disease. The researchers identified a process by which autophagy was overactivated and molecules necessary to repair DNA are degraded, ultimately leading to cell death.

In particular, the study focused on the C9orf72 gene, which consists of a six-basepair sequence usually repeated between 2 and 30 times. A mutation that increases the repetition to the order of hundreds has been identified as the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. However, it is not well understood how the mutation causes neurodegeneration.

ALS Research C9orf72 gene

Using animal models and cells from ALS patients, the scientists determined that these DNA repetitions interact with RNA, forming R-loops that leave DNA susceptible to damage. They found an increased rate of double-strand breaks, which overactivated autophagy in the cells and resulted in the degradation of DNA repair pathways necessary to keep the cells alive.

By tuning up the activity of this pathway, the researchers could prevent the death of neurons. “We were able to shut down the out-of-control degradation process, which runs down the cell’s ability to fix genomic breaks, using genetic techniques,” said in a statement Professor El-Khamisy, who co-directed the study. “Even though the DNA was still damaged, the cells were able to cope and did not die.

These results are very valuable in providing a deeper insight into a process that is still poorly understood. The lack of knowledge has hindered the development of effective therapies for neurodegenerative diseases such as ALS and motor neuron disease, for which there is no treatment available.

More research needs to be done, but it’s possible that this newly discovered mechanism contributes to the death of nerve cells in people suffering from diseases such as Alzheimer’s, Parkinson’s and during the aging process,” said El-Khamisy,  “I’m really excited, if we modulate this degradation process, we can preserve our DNA repair toolkit and take away the pathology, the cell death.

Images via Kjpargeter; Rohrer JD et al. The Lancet Neurology. Volume 14, Issue 3, March 2015, Pages 291-301

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