CUHK research unveils novel disease mechanisms of amyotrophic lateral sclerosis and opens up new treatment paths
- A CUHK research team finds that the signalling pathway activated by perturbed transcriptional factor YY1 in neurons can cause ALS. It can be used as a drug target to treat this incurable disease.
- The HKNMDA has established an ALS patient registry, which shows that it takes an average of nearly a year for patients to be diagnosed, and most of them are severely disabled. The association calls for the provision of rehabilitation services for ALS patients.
Collaborating with the University of Oxford, Professor Edwin Chan Ho-yin’s research team from the School of Life Sciences at The Chinese University of Hong Kong (CUHK) has recently uncovered a novel molecular mechanism that leads to the pathogenesis of amyotrophic lateral sclerosis (ALS). The research findings have been published in the prestigious scientific journal Nature Communications. This work was also awarded the Oral Poster Presentation Award – Basic Science First Prize at The Pan-Asian Consortium for Treatment and Research in ALS (PACTALS) 2023 Congress.
ALS is an adult-onset neurodegenerative disease that impacts the brain and spinal cord, causing muscle weakness, loss of coordination and ultimately respiratory failure. The incidence of ALS is 4.4 per 100,000 people globally. To date, ALS remains incurable.
Mechanistic investigations are critical to better understand ALS pathogenesis
To identify ALS therapeutic targets, Professor Edwin Chan Ho-yin, Postdoctoral Fellow Dr Stephen Chen Zhefan and the team studied the underlying mechanisms of gene transcriptional control in ALS. The team demonstrated that the function of a transcriptional factor Yin Yang 1 (YY1) is perturbed in ALS patient spinal motor neurons. Such perturbation downregulates the expression of YY1’s target gene Fuzzy, and this subsequently induces the Wnt/β-catenin pathway and consequently leads to neuronal cell death. The identification of YY1-Fuzzy-Wnt/β-catenin signalling offers additional mechanistic insights into ALS pathogenesis.
The findings unveil new targets for therapeutic ALS developments
The team showed that when this pathogenic pathway was inhibited, the cellular dysfunction of ALS patients’ spinal motor neurons was ameliorated. This highlights the identified pathway as a potential druggable target for the treatment of ALS neurotoxicity. The research team led by Professor Chan is now screening new drug candidates and testing their efficacy at suppressing neuronal cell death in both the cell and fly ALS models. The team plans to test promising drug candidates on rodent and primate models to further evaluate their effectiveness.
Professor Chan said, “Currently, there is no effective treatment to cure ALS patients. Elucidating the underlying disease mechanisms will not only allow us to better understand ALS pathogenesis but, more importantly, will also direct the development of new drug candidates against this devastating neurodegenerative condition. We believe that our work will provide additional angles for developing therapeutic ALS interventions.”
The first ALS patient registry reveals the conditions and needs of patients
The Hong Kong Neuro-Muscular Disease Association (HKNMDA) recently established Hong Kong’s first ALS patient registry with the assistance of medical student volunteers, to understand the conditions and needs of patients. The database has collected data from a quarter of all ALS patients in Hong Kong.
Mr Lui Man-lam, President of the HKNMDA, stated, “According to our survey, patients develop symptoms on average at the age of 55, with initial symptoms of weakness in the hands and feet [53% and 42%, respectively]. Due to the difficulty of recognising early symptoms, patients consult four doctors and undergo five detailed examinations on average [such as electromyography, nerve biopsy, bone marrow aspiration and so on] before being diagnosed with ALS. It takes an average of nearly a year, with 12% taking over two years. Two-thirds of patients are now severely disabled, with their daily functional ability being only one-third of late-stage cancer patients. Most patients develop symptoms at the age of 50 or above, and the survival time varies from a few months to 10 years, with a median of three years.”
Rehabilitation therapy is crucial, and the association hopes for rehabilitation support
Currently, there is no effective medication for ALS. Patients’ thinking and senses are not affected, and they can clearly feel the rapid deterioration of their physical functions. Fortunately, there are rehabilitation treatments available that can effectively alleviate symptoms, reduce complications and maintain quality of life. Ms Sae Sow Jintana, Centre-in-charge of the HKNMDA, said, “Many patients not only want to survive but also hope to live with dignity, and continue to move and enjoy time with their loved ones. Currently, there are various assistive and non-invasive treatments, as well as types of surgery, that can help relieve symptoms in patients. Appropriate technology and rehabilitation support, such as seemingly simple carbon fibre ankle braces and a sputum aspirator, have been of great assistance to patients.”
Ms Sae Sow points out that some patients have been living with the disease for 10 years, adding that she encourages them to face it actively. While awaiting breakthrough treatments, the HKNMDA urges all sectors to provide support to fund rehabilitation services and purchase assistive devices. It also calls on the government to promptly establish specialised clinics for neurological-muscular diseases and provide rehabilitation services, assistive devices and comprehensive care for patients.
 Source: Xu et al. (2020) J Neurol. 267, 944-953