Study reveals pathological mechanisms of synaptic dysfunction in patients with Huntington’s disease

Huntington’s disease (HD) is an inherited brain disease caused by a mutation in the huntingtin gene. HD is an incurable neurodegenerative disease which, after the onset of the disease around the age of 40, causes personality changes and symptoms of dementia as well as uncontrollable twitching, ultimately leading to death. These HD symptoms are known to be caused by the destruction of brain cells in the striatum due to problems occurring in the synapses that are essential for brain function as the disease progresses. However, the specific mechanism behind brain dysfunction during HD progression has not been fully elucidated.

The research team led by Dr. Jihye Seong and Dr. Hoon Ryu, senior researchers at the Brain Science Institute (BSI) of the Korea Institute of Science and Technology (KIST, President Seokjin Yoon), reportedly found a Significantly reduced activity of adhesion proteins kinase (FAK) which play an important role in neurite motility and proper synapse formation in the brain tissues of HD patients.

Activated FAK proteins play an important role in brain function as they are essential for 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 in brain tissue from HD patients. These results were also verified by precise measurements of FAK activity in living cells using a fluorescence resonance energy transfer (FRET) based biosensor.

Phosphatidylinositol 4,5-biphosphate (PIP2), a phospholipid present 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 tightly bound to the mutant huntingtin protein, inhibiting the proper distribution of PIP2 throughout the cell membrane. This abnormal distribution of PIP2 inhibits the activation of FAK, which impairs proper synaptic function, causing brain dysfunction in the early stages of HD.

The pathological mechanisms of synaptic dysfunction in patients with Huntington’s disease revealed by this study could be used as a therapeutic target for the treatment of brain dysfunction. ยป

Dr. Jihye Seong, Brain Science Institute (BSI), Korea Institute of Science and Technology

Dr Ryu said: “Because the results of this study show the disease mechanisms found in actual brain tissue from HD patients, I believe it has greater significance in suggesting a novel therapeutic target for brain disease. human degenerative diseases.”

Source:

Korea Institute of Science and Technology

Journal reference:

Lee, HN, et al. (2022) Decreased FAK activity and focal adhesion dynamics impair proper neurite formation of medium spiny neurons in Huntington’s disease. Acta Neuropathological. doi.org/10.1007/s00401-022-02462-z.

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