Researchers uncover new role of Huntington’s disease protein in maintaining cell structure

Huntington’s disease, one of the most devastating hereditary neurodegenerative disorders, robs patients of motor control, cognitive function, and mental stability, with no cure currently available.

An international team of researchers, including the Korea Advanced Institute of Science and Technology (KAIST), has shed new light on the disease by discovering that the protein at the center of Huntington’s disease, huntingtin, is not only altered in patients but also plays a vital role in maintaining the cell’s structural framework.

The findings, published Sept. 19 in Science Advances, reveal that huntingtin organizes actin filaments -- the scaffolding fibers inside cells -- into orderly bundles, a process essential for the development of neural networks. Until now, huntingtin had been known primarily for assisting in intracellular transport.

Using cryo-electron microscopy and cellular biology techniques, the KAIST group, together with Austria’s Institute of Science and Technology (ISTA), Sorbonne University and the Paris Brain Institute in France, and Switzerland’s École Polytechnique Fédérale de Lausanne (EPFL), demonstrated how huntingtin directly binds to actin filaments.

Professors Song Ji-joon and Kim Hyeong-ju and Ph.D candidate Kim Jae-sung participated from KAIST.

The protein works in pairs, spacing the filaments roughly 20 nanometers apart to create tightly bundled structures.

These cytoskeletal bundles were shown to be critical for neuronal development. In nerve cells lacking huntingtin, researchers observed impaired structural growth, highlighting the protein’s importance beyond previously recognized functions.

“This study offers a new perspective on the molecular mechanism of an incurable disease,” Kim Jae-sung said.

Professor Song also said, “This achievement not only provides crucial clues for understanding the pathogenesis of Huntington’s disease but also has far-reaching implications for other conditions related to cytoskeletal dysfunction, such as Alzheimer’s disease, Parkinson’s disease, and muscular dystrophy.”

The work, carried out with support from Korea’s Ministry of Health and Welfare through its Global Research Collaboration and international cooperative programs with Switzerland and Austria, marks the first structural-level demonstration of huntingtin’s organizing role in the cytoskeleton.