KAIST Unveils Hidden Role of 'Huntingtin Protein'... "Contributing to Degenerative Disease Research"

A new study has revealed that the Huntingtin protein (Huntingtin, hereafter HTT) plays a crucial role in the growth of neurons and the maintenance of the cytoskeletal structure.

HTT is known as the causative protein for Huntington’s disease and has so far been primarily understood as a platform that assists intracellular vesicle transport. However, recent research has reported that the deficiency or mutation of HTT affects the function of the cytoskeletal protein “F-actin.”

Additionally, there have been indications that HTT may play a key role in the growth process at the axon terminals of neurons. However, the direct interaction and structural basis between HTT and F-actin had not been clearly identified.

In contrast, this latest study has elucidated how HTT regulates F-actin and what this regulatory function means for neuronal development.

Huntington’s disease is a representative neurodegenerative disorder (a rare genetic disease) characterized by loss of muscle coordination, cognitive decline, and psychiatric symptoms. There is growing anticipation that these research findings may contribute to future studies on other degenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and muscular dystrophy.

(From left) Professor Ji-Jun Song of the Department of Life Science, PhD candidate Jae-Sung Kim, and PhD Hyung-Joo Kim. Provided by KAIST

KAIST announced on October 1 that a research team led by Professor Ji-Jun Song from the Department of Life Science, in collaboration with the Institute of Science and Technology Austria (ISTA), Sorbonne University and the Paris Brain Institute in France, and the Swiss Federal Institute of Technology Lausanne (EPFL), has uncovered the structural principle by which HTT arranges F-actin into bundled forms, using cryo-electron microscopy (cryo-EM) and cell biological techniques.

Until now, HTT was thought to be limited to “using” the cytoskeleton, such as participating in vesicle transport and microtubule-based trafficking. In contrast, the joint research team newly discovered that HTT physically organizes the cytoskeleton itself. This study is considered the world’s first to demonstrate the previously unknown molecular-level function of HTT.

The joint research team confirmed that HTT not only binds directly to F-actin, but also that two HTT molecules pair up to neatly bundle the cytoskeleton at 20-nanometer intervals.

Mechanism of Huntingtin Protein in Cytoskeletal Microfilament Bundle Formation and Its Impact on Neuronal Development Revealed. Provided by KAIST

The cytoskeletal bundles formed through this process play a key role in the development of neuronal networks. In fact, neurons deficient in HTT exhibited impaired structural development.

Jae-Sung Kim, PhD candidate, said, “Through this study, we have presented a new perspective for understanding the mechanism of action of the protein that causes Huntington’s disease, which has long been shrouded in mystery and regarded as incurable.”

Professor Song stated, “This research not only provides an important clue for understanding the mechanism of Huntington’s disease, but is also expected to have significant ripple effects in the study of cytoskeleton-related diseases. It opens new avenues for illuminating the role of HTT in various biological phenomena such as cell division, migration, and mechanical signal transduction.”

This research was conducted with Jae-Sung Kim, PhD candidate at KAIST; Hyung-Joo Kim, PhD (currently at Harvard University); Remi Carpentier, researcher at the Paris Brain Institute; and Mariacristina Capizzi, researcher, as co-first authors.

The results were recently published in Science Advances, a sister journal of Science.

This content was produced with the assistance of AI translation services.