DNA repair is an important topic when talking about of neurodegenerative disorders. The amount of biochemical stress the brain experiences increases naturally as we age. Some connections have been made between the amount of stresses on the brain and the age people develop neurodegenerative disorders.
Many of these natural stresses can damage DNA. For this reason, many researchers are trying to find ways of helping or fixing DNA repair. Chemicals that effect DNA repair could be used as new drugs. Here, we will focus on just one part of the DNA damage response that has been a great success in cancer drug discovery.
PAR is like a net that pulls in proteins that repair DNA
Poly-ADP-ribose, also called PAR, are long molecules in the cell. They are made of of the same building blocks cells use to store enegry. PARylation is when these long chains of PAR are made and attached to different parts of the cell. This happens in response to many different types of stress. For example, a stress could be if a cell’s DNA is damaged or it is infected with a virus.
When DNA damage happens, PAR molecules are attached on the surface of proteins and can act as a basket to trap other proteins. PAR is made and woven together by PAR polymerase proteins (called PARPs). PARPs add PAR chains all around a site of damage to let other parts of the cell know that damage has happened. This attracts DNA repair proteins to DNA damage by binding to PAR and performing their role to fix the damage.
To much PAR causes cells to run out of energy
Even though PAR does a good job of signalling that DNA damage has happened, it takes a lot of energy to make. If the damage can not be fixed, the cell will keep trying to make PAR until runs out of energy. This can lead to PAR molecules causing cell death. This effect of too much PAR can be seen in multiple types of neurodegenerative diseases.
A type of cerebellar ataxia called AOA-XRCC1 is known for having higher levels of PAR due to DNA damage. When researchers reduced the amount of PAR in a mouse model of AOA-XRCC1, the mouse had fewer ataxia symptoms and lost fewer neurons. This type of ataxia is caused by a mutation in a protein called XRCC1, which normally helps fix DNA and binds to PAR chains. But in the disease, the XRCC1 gets stuck at DNA along with the long chains of PAR.
These findings may be applicable to other types of ataxia and neurodegenerative disorders because of their link to higher levels of DNA damage. A lot more work to be done on PARylation and its role in neurodegeneration. But a lot of research has been done on PAR in cancer. Many drugs have been FDA approved for cancer patients as safe and effective. Cancer and ataxia are very different diseases. But all the work that has previously been done has laid the groundwork for new research in neurodegeneration.
Snapshot written by Carlos Barba-Bazan and edited by Dr. Ray Truant
Hoch, Nicolas C., et al. “XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.” Nature 541.7635 (2017): 87-91. https://www.nature.com/articles/nature20790
Atasheva, Svetlana, et al. “New PARP gene with an anti-alphavirus function.” Journal of virology 86.15 (2012): 8147-8160. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3421642/
Andrabi, Shaida A., et al. “Poly (ADP-ribose)(PAR) polymer is a death signal.” Proceedings of the National Academy of Sciences 103.48 (2006): 18308-18313. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1838747/