Huntington’s disease (HD) is a hereditary brain condition caused by a huntingtin gene mutation. It is a fatal neurological condition with no treatment that causes personality changes, dementia symptoms, and uncontrollable convulsive movements. Such HD symptoms are known to be caused by the loss of brain cells in the striatum as a result of issues arising in synapses that are crucial to brain function throughout the advancement of the illness. However, the specific mechanism of brain dysfunction during HD is yet unclear.
The findings of the study were published in the journal Acta Neuropathologica. The research team lead by Dr. Jihye Seong and Dr. Hoon Ryu, principal researchers at the Brain Science Institute (BSI) of Korea Institute of Science and Technology (KIST, President Seokjin Yoon), was said to have found significantly reduced activity of focal adhesion kinase (FAK) proteins that play an important role in neurite motility and proper synapse formation in the brain tissues of patients with HD.
Activated FAK proteins play an important role in brain function as they are essential in neurite motility and proper synapse formation. The KIST research team identified a significant reduction in FAK activity in HD cells and mouse models, as well as brain tissues of HD patients. These results were also verified through accurate measurements of FAK activity in live cells using a fluorescence resonance energy transfer (FRET)-based biosensor.
Phosphatidylinositol 4,5-biphosphate (PIP2), a phospholipid found in the cell membrane, is essential for the activation of FAK proteins. Using super-resolution structured illumination microscopy, the research team found that PIP2 in HD cells was unusually strongly bound to the mutant huntingtin protein, inhibiting proper distribution of PIP2 throughout the cell membrane. This abnormal distribution of PIP2 inhibits FAK activation, which hinders proper synaptic function, causing brain dysfunction in the early stages of HD.
Dr. Seong said, “The pathological mechanisms of synaptic dysfunction in patients with Huntington’s disease revealed through this study could be utilized as a therapeutic target for the treatment of brain dysfunction.”
Dr. Ryu said, “Because the results of this study show the pathological mechanisms found in actual brain tissues of patients with HD, I believe it has a greater significance in suggesting a new therapeutic target for human degenerative brain diseases.”