The Role of Chromatin and DNA Damage in Neurodegenerative Disorders

St. Jude Children’s Research Hospital has recently been conducting research on pediatric neurodegenerative disorders defined by mutations that affect DNA repair proteins and trigger progressive loss of Purkinje cells. The main two diseases they focused their research on were ataxia telangiectasia (A-T) and ataxia with oculomotor apraxia 1 (AOA1), which involve issues with motor skills typically coordinated by Purkinje cells. Their latest findings were recently published in Science Advances.

This study cited our popular Anti-DNA-RNA Hybrid [S9.6] Antibody from the lab of Stephen H. Leppla, PhD at the National Institute of Allergy and Infectious Diseases/NIH for the detection of R loops without cross-reactions with single-stranded or double-stranded DNA.

Purkinje Cells

Located in the brain across many species, Purkinje cells are involved in coordinating motor control and transmitting important messages between the cerebellum and the cerebral cortex. The bulk of Purkinje cells are located in the cerebellum, which is responsible for physical movement in the body. It has been found that instability with these cells may be the cause of a range of neurodegenerative disorders. These diseases are characterized by damage to cells that slowly results in the loss of motor function such as movement, coordination and strength.

The Study

Scientists from St. Jude Children’s Research Hospital utilized a mouse model developed onsite to investigate why Purkinje cells are susceptible to progressive neurodegeneration and ataxia. The study pointed them toward DNA repair proteins as the culprit for the mutations affecting Purkinje cells.

Mutated DNA repair proteins caused a disruption in the transcription and gene expression process in Purkinje cells, ultimately leading to further DNA damage such as R-loops. R-loops are three-stranded DNA-RNA structures that left unrepaired will continue to progress the damage even further.

The team then shifted their focus to how the gene expression process is affected by chromatin. Chromatin packages DNA and proteins, and open chromatin architecture makes DNA more accessible for transcription, therefore promoting gene expression. Upon looking further into the role of chromatin in the cerebellum, an architectural issue was uncovered: the genome regions with open chromatin architecture were found to be the most susceptible to damage. These regions were the home of mutant DNA repair proteins, leading to the formation of R-loops and gene expression issues in Purkinje cells.

Understanding Neurodegenerative Diseases

DNA repair mutations have been found in a variety of similar neurodegenerative diseases, and although there are still questions about the disease processes, the architectural vulnerability identified in this study may lend an explanation to why certain cell types are lost as the disease progresses. This study could pave the way for a greater understanding of this range of diseases and hopefully a potential cure in the future.

Our Anti-DNA-RNA Hybrid [S9.6] Antibody used in this study is available for purchase worldwide from the Kerafast catalog here. You also might be interested in our lab-made reagents for studying DNA damage/repair or neurobiology, such as: