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 NeuroscienceÂ describes a previously unknown mechanism behind the death of neurons in neurodegenerative disease. The researchers identified a process by which autophagy was overactivatedÂ andÂ molecules necessary to repair DNA areÂ degraded, ultimately leading toÂ cell death.
In particular, the study focused onÂ theÂ C9orf72 gene, which consists of aÂ six-basepair sequence usually repeated between 2 and 30 times. AÂ mutation that increases the repetition to the order of hundredsÂ has been identifiedÂ as the most common causeÂ of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. However,Â it is not well understood how the mutation causes neurodegeneration.
Using animal models andÂ cells from ALS patients, the scientistsÂ determined that these DNA repetitions interact withÂ RNA, forming R-loops that leave DNA susceptible toÂ damage. They foundÂ an increased rate ofÂ double-strand breaks, which overactivatedÂ 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.Â âWe were able to shut down the out-of-control degradation process, which runs down the cellâs ability to fix genomic breaks, using genetic techniques,â said in a statement Professor El-Khamisy,Â who co-directed the study.Â âEven 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…