Mitochondrial Protein That “Erases” Huntington’s Aggregates

DGIST has made a groundbreaking announcement: a research team, under the guidance of professors Jiwon Um and Jaewon Ko, has achieved a global first by explaining the function of ‘ClpB.’ This mitochondrial protein plays a direct role in dissolving and eliminating toxic protein aggregates, which are a primary cause of Huntington’s disease.

Image credit: Orawan Pattarawimonchai/Shutterstock.com

This finding proposes a novel approach to treating degenerative brain diseases, demonstrating the potential to remove accumulated protein aggregates in the brain and even rehabilitate impaired nerve cell functions.

Huntington’s disease is a prevalent inherited degenerative brain condition, carrying a 50 % chance of transmission from parents. It manifests as gradual memory loss or motor impairments that disrupt daily life. Despite the anxieties faced by many patients and families wondering if their children might inherit the disease, current treatments are unable to halt its progression or reverse existing symptoms.

Prior research has largely concentrated on preventing protein aggregation. While some treatments have shown efficacy in slowing or stopping protein aggregation, they have limitations in directly dissolving large aggregates that have already formed.

In response to these limitations, the research team centered its investigation on the ‘ClpB’ protein, which functions within mitochondria, the cell's energy-producing units. While ClpB has been known to disassemble protein clumps under stress conditions like heat exposure, its ability to actively break down toxic proteins and restore neurological function in the pathological environment of brain disease was previously unknown.

Schematic diagram of the molecular role of ClpB in Huntington's disease model mice. Image Credit: Daegu Gyeongbuk Institute of Science and Technology

The team employed a Huntington's disease cell model and a mouse model to meticulously control ClpB expression and examine its function. The results indicated that the absence of ClpB led to the easy aggregation of even normal Huntington protein, thereby increasing cell damage. Conversely, elevated ClpB levels directly disassembled and reduced the toxic clumps of mutant Huntington protein.

This accomplishment holds significant implications for Huntington's disease and the treatment of various neurodegenerative disorders where protein aggregation is a central factor, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS).

The protein's ability to directly disassemble existing protein aggregates is a key discovery that may pave the way for a new therapeutic strategy focused on restoring damaged neuronal functions, surpassing the limitations of current prevention-centered approaches.