A Korean research team said they found the cause of brain dysfunction in patients with Huntington’s disease (HD).

HD is a hereditary neurodegenerative disorder that usually starts around 40. It causes uncontrolled jerky body movements, personality changes, and dementia symptoms. It eventually leads to death, but there is no cure.

On Sunday, the Korea Institute of Science and Technology (KIST) said its research team, led by researchers Seong Ji-hye and Ryu Hoon at KIST’s Brain Science Institute, discovered that the activity of focal adhesion kinase (FAK) was significantly reduced in brain tissues of HD patients. FAK plays an important role in neurite motility and normal synaptic functions.

The research team measured FAK activity in living cells using a molecular fluorescence sensor based on Fluorescence Resonance Energy Transfer (FRET) and verified this.

Proposed model of the impaired FAK activity in HD (Credit: KIST)
Proposed model of the impaired FAK activity in HD (Credit: KIST)

For a normal activity of FAK, phosphatidylinositol 4,5-biphosphate (PIP2) is essential among phospholipids in the cell membrane.

However, in the cells with HD, PIP2 was abnormally distributed, the research team said.

The research team used super-resolved structured illumination microscopy to find that PiP2 bound to mutant huntingtin (mHTT) protein abnormally and could not be normally distributed in the cell membrane.

The abnormal distribution of PIP2 inhibited FAK activity in HD, and the reduced FAK activity disrupted the normal synaptic functions. The research team said this is the cause of brain dysfunction in early HD.

“The pathological mechanism of synaptic dysfunction in HD patients, discovered in this study, can be used as a therapeutic target to recover brain dysfunction during the progression of HD,” said Seong.

Ryu noted that the study results demonstrated the pathological mechanism in the brain of HD patients, suggesting a new treatment target for human degenerative brain diseases.

The study, titled “Decreased FAK activity and focal adhesion dynamics impair proper neurite formation of medium spiny neurons in Huntington’s disease,” was published in the latest issue of Acta Neuropathologica.

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