Huntingtin Protein’s New Role in Cytoskeleton Organization Reveals Insights into Neurodegenerative Diseases

Huntington's disease is a rare genetic disorder classified as a neurodegenerative condition, characterized by progressive motor dysfunction, cognitive decline, and psychiatric symptoms. Recent groundbreaking research conducted by an international team has uncovered a new fundamental role of the huntingtin protein, the main protein involved in causing Huntington's disease. Traditionally known for its involvement in vesicle and microtubule-based transport within cells, huntingtin has now been shown to directly organize the cell's cytoskeleton.

Using advanced cryo-electron microscopy (cryo-EM) and cell biology techniques, scientists from KAIST, ISTA, Sorbonne University, and EPFL demonstrated how huntingtin proteins bind directly to cytoskeletal microfilaments (F-actin). They revealed that huntingtin facilitates the bundling of these filaments into organized arrays with an interval of about 20 nanometers, which are crucial for neural connectivity development. This structural organization appears to impact neuronal growth, as nerve cells lacking huntingtin exhibit impaired neuron development.

The research team demonstrated that huntingtin physically interacts with actin filaments, promoting their bundling into functional structures. This discovery is significant, as it provides the first molecular-level evidence of huntingtin’s role in shaping the cytoskeleton, a function previously unrecognized. The findings, published in Science Advances, suggest that disruptions in this capacity of huntingtin might contribute to the pathogenesis of Huntington's disease.

Furthermore, this new understanding may extend beyond Huntington's, informing research into other neurodegenerative and muscular disorders such as Alzheimer’s disease, Parkinson’s disease, and muscular dystrophy. The study opens avenues for exploring how huntingtin is involved in cell division, migration, and mechanical signal transduction, expanding our understanding of its biological functions.

First author Jaesung Kim emphasized that this work provides a novel perspective on the molecular mechanisms underlying Huntington's disease, offering potential pathways for future therapeutic research. Professor Ji-Joon Song highlighted that these insights could lead to a broader understanding of cytoskeleton-related diseases and help develop strategies targeting the structural organization within cells.

This pivotal discovery not only enhances our understanding of neurodegeneration but could also influence a wide range of biomedical research focused on cell structure and function.