Huntington’s disease is a genetic disorder that kills nerve cells in the brain, causing people to lose their cognitive and motor abilities. New research led by Thomas Jefferson University researcher Anna Pluciennik, PhD is revealing the molecular pathways behind the disease. Along with graduate researcher Fenglin Li, research associate Ashutosh Phadte, and postdoctoral research fellow Mayuri Bhatia, she and the rest of her team found a protein complex that fixes abnormal DNA and could be a potential target for Huntington’s disease.
Huntington’s is characterized by an abnormal repeating sequence in the DNA. As people with Huntington’s age, this sequence gets longer, causing the strands of DNA to misalign, like a shirt with its buttons in the wrong holes. This misalignment creates extra loops in the DNA that make the DNA longer and longer. This in turn leads to the production of a toxic protein which eventually kills nerve cells.
Prior research showed small mutations in a protein called FAN1 could hasten or delay the onset of Huntington’s disease. Dr. Pluciennik believed FAN1 may play an important role in removing these extra loops of DNA, so the research team set out to test the theory.
Using an electron microscope to generate “pictures” of FAN1 interacting with DNA, the team found that the protein acted like a pair of scissors, snipping off extra loops of abnormal DNA. To do this, FAN1 teamed up with another protein, called PCNA, forming a stable complex. Dr. Pluciennik found the same mutations that were associated with earlier disease onset also impacted the stability of the FAN1-PCNA complex, making it less effective at removing extra pieces of DNA, like scissors with dull blades.
“Based on our research, if you made the FAN1-PCNA complex more stable, or made more of the FAN1 protein, it could be protective and delay disease onset,” says Dr. Pluciennik, a member of the Sidney Kimmel Medical College.
In addition to helping researchers understand the molecular basis of Huntington’s, this research positions the FAN1-PCNA complex as a promising therapeutic target.