The Fudan research team has brought a new dawn to incurable neurological diseases

Like the familiar Alzheimer's disease (AD) and Parkinson's disease (PD), Huntington's disease (HD) is a neurodegenerative disease. The pathogenesis of each of these diseases is related to the misfolding of proteins. Although the specific pathogenic proteins involved are different, they will accumulate in nerve cells, accumulate over time, and eventually poison nerve cells, resulting in functional disorders in many aspects such as movement and cognition.

Finding ways to reduce and eliminate disease-causing proteins in cells is an important idea for the treatment of such diseases. To that end, scientists began experimenting with emerging biological tools, such as gene-edited CRISPR, antisense RNA, and targeting HD's disease-causing protein, the mutant huntingtin protein (mHTT).

In this study, a team led by Prof. Lu Bocheng, Prof. Ding and Prof. Fei Yiyan proposed a new way to clear mHTT: using the cell's own protein degradation system, autophagy.

When it comes to autophagy, everyone may be familiar with it. In 2016, Japanese scientist Yoshinori Osumi won the Nobel Prize in Physiology or Medicine for his discovery of the mechanism of autophagy. This physiological process is ubiquitous in eukaryotes, where cells use lysosomes to remove and degrade their own cellular structures, senescent organelles, and biomacromolecules that are no longer needed, and autophagy can be said to be like a "waste recycling station" within the cell

The Fudan research team's idea is to throw the disease-causing protein of HD into the waste recycling bin in the cell. In order to precisely target the disease-causing protein without accidentally harming the "innocent"—especially the normal HTT protein, which carries a neuroprotective function—the researchers envisioned a strategy of "small molecule binding compounds," which they called "small molecule glue."

Specifically, specific small molecules are used to "stick" a key protein LC3 in the autophagy process with the pathogenic protein, thereby promoting the specific degradation of the pathogenic protein.

The multidisciplinary team used a novel high-throughput drug screening platform to find 2 small molecules that met the requirements from nearly 4,000 small molecule compounds. Then, by detecting small molecules with similar structures, the research team obtained a total of 4 theoretically feasible "small molecule glues".

Specifically, specific small molecules are used to "stick" a key protein LC3 in the autophagy process with the pathogenic protein, thereby promoting the specific degradation of the pathogenic protein.

The multidisciplinary team used a novel high-throughput drug screening platform to find 2 small molecules that met the requirements from nearly 4,000 small molecule compounds. Then, by detecting small molecules with similar structures, the research team obtained a total of 4 theoretically feasible "small molecule glues".

So, what is the actual combat effect of these 4 compounds? A series of experiments have shown that these compounds can significantly reduce mHTT levels in cultured mouse neurons and cells of HD patients, as well as in HD fruit flies and mouse models, while maintaining normal HTT levels.

Despite the promising positive results in animal experiments, Professor Huda Zoghbi, a well-known scientist in the field of neurodegenerative diseases, pointed out in a review that the next step is "long-term preclinical trials in mice to determine their long-lasting and stable efficacy in long-term treatment."

If it can be clinically proven effective against HD, "the drug discovery strategy of autophagysome-bound compounds is also expected to be applied to other disease-causing proteins that are difficult to target and even non-protein pathogenic substances." Professor Lu Bocheng is full of expectations for the future application of this achievement.

We congratulate scientists on this achievement in the battle for neurodegenerative diseases, and look forward to the follow-up research progress to benefit patients as soon as possible."