There is currently no cure for this disease. Scientists in Zhejiang Province have brought new ideas to the treatment of this "rare disease"

Initially, there are mild motor disorders, and running, jumping and other movements become difficult. Later, the patient gradually becomes unable to walk and cannot lift his limbs normally, and needs to use a wheelchair to move around. Eventually, he may die of respiratory failure or heart failure...

This passage describes the life of a patient with Duchenne muscular dystrophy. Duchenne muscular dystrophy (DMD), referred to as DMD, is a serious hereditary neuromuscular disease and one of the most common fatal genetic diseases.

Unfortunately, there is currently no cure for this disease.

Recently, Zhejiang scientists, a research team from West Lake University, have made new breakthroughs in the research of the core protein of the disease.

On December 11, 2024, Beijing time, Wu Jianping's team from Westlake University and Westlake Laboratory and Yan Zhen's team jointly published a paper titled "Structure and assembly of the dystrophin glycoprotein complex" in Nature online. The team "saw" the core protein of muscular dystrophy for the first time, unveiled the mystery of the dystrophin glycoprotein complex (DGC), and demonstrated its unique structural characteristics.

| Screenshot of the paper

This study fills an important gap in the field that has existed for nearly three decades. This discovery provides new insights into the pathogenesis of muscular dystrophy.

What is Duchenne muscular dystrophy (DMD)?

According to statistics, there are more than 300 million patients with rare diseases in the world, and more than 20 million patients with various rare diseases in China. DMD is one of these rare diseases.

In 1986, American scientists discovered that the cause of DMD is a defect in the dystrophine gene. Since the DMD gene is located on the X chromosome, DMD mostly occurs only in boys, with an incidence rate of about 1 in every 3,500 boys.

| DMD clinical manifestations Source: Westlake University

DMD patients will experience progressive skeletal muscle weakness and degeneration, with a high mortality rate. They often experience symptoms such as bradykinesia, abnormal gait, and difficulty standing at the age of 3 to 5, which gradually worsen with age. They need to rely on wheelchairs to travel at around 12 years old, and may die of cardiopulmonary failure at around 20 years old.

Because the disease still cannot be cured, finding safe and effective treatments has always been the ultimate goal of research in this field.

This core protein

What causes DMD?

One of the protagonists of this study is a protein called Dystrophin, which is the full name of dystrophin. It is an important cytoskeletal protein that mainly exists in skeletal muscle and cardiac muscle cells and plays a vital role in maintaining the structure and function of muscle cells.

When Dystrophin interacts with multiple proteins in the body, it forms the DGC complex. This complex is mainly distributed in muscle tissue and the nervous system. Muscular dystrophy is related to mutations in this protein complex.

If muscle cells are a tall building, then the DGC complex is both the building's "shock absorber" and "communication equipment". It is the link between the inside and outside of the cell, which can absorb and disperse the mechanical force generated by muscle contraction, thereby helping to protect and maintain the integrity and stability of the muscle cell membrane. At the same time, the DGC complex also has the function of signal transduction, affecting cell growth, differentiation and survival.

| High-resolution electron density map of the endogenous DGC complex in skeletal muscle Source: West Lake University

First time seeing clearly

The “True Face” of Core Protein

Wu Jianping's team and Yan Zhen's team from the School of Life Sciences of Westlake University successfully isolated the natural endogenous DGC complex from mouse skeletal muscle tissue, and used cryo-electron microscopy technology to resolve its high-resolution structure (resolution 3.2-3.5 Å), providing the first clear picture of the entire complex and filling a nearly three-decade gap in this field.

Afterwards, the research team returned to the disease itself and studied where the pathogenic mutation sites associated with muscular dystrophy are. They analyzed a large amount of mutation site data related to muscular dystrophy accumulated in clinical studies over the past few decades and found that the pathogenic mutations associated with muscular dystrophy are mostly distributed in three regions. These specific regions play an important role in the normal function of DGC, providing in-depth insights into the pathogenic mechanism of related muscular dystrophy.

| Research team Image source: Westlake University

From the microscopic perspective, there are new clues for developing gene therapy solutions. Currently, there are very limited treatment options for DMD patients. A common strategy is to repair the dysfunctional dystrophin protein through gene therapy. However, the gene for this protein is one of the longest genes in the human body, and it is very difficult to deliver such a long gene in its entirety to replace the disease-causing gene.

The research results from Westlake University provide an important reference for designing more reasonable and effective protein delivery. In the future, the important clues provided by this structure may bring new hope for the treatment of muscular dystrophy.

(Source: Chao News, Westlake University)