There is still much we do not know about the biological processes that take place in our bodies. But, understanding how our body functions at the molecular level is essential if we are to understand the causes of diseases and find ways to treat them.

Thanks to its frequent exposure in popular culture in the past decade, from crime forensic dramas to science fiction movies, the term ‘DNA’ (Deoxyribonucleic acid) and its role as a container of genetic code for all living beings has by and large entered the everyday lexicon and consciousness of the general public. However, almost none of us will have come across ‘RNA’ (Ribonucleic acid), another form of nucleic acid that has the essential roles of transmitting genetic information contained in DNA and to synthesize proteins. Without proteins there is no cell formation. Without cells there is no life.

Spinocerebellar Ataxia — A Debilitating Disease

People live their lives without giving RNA a second thought. But for some, the failure of RNA to transmit genetic code properly is a cause of spinocerebellar ataxias (SCAs), a group of incurable diseases that leads to the progressive deterioration of the cerebellum, which is the region of the brain responsible for motor control and coordination. Sufferers will lose the ability to move their bodies over time, have difficulty maintaining balance or coordinating basic daily movements, and have slurred speech as they lose control of their facial muscles. Some eventually become wheelchair-bound.

‘SCA is a disease that can strike both young and old and can occur suddenly or develop over time. It can be inherited from parents or acquired from an external source. It has no cure and current treatments can only slow down the damage to the cerebellum by alleviating the symptoms,’ said Prof. Chan Ho-yin Edwin in the School of Life Sciences. He has dedicated himself to the study and research on the pathogenic pathways of SCAs in the hope of finding the causes of SCA. In doing so, he hopes that a cure to the disease can eventually be found and developed.

In a normal, healthy adult, around 50 to 70 billion cells die each day in a natural process called ‘apoptosis’ (i.e., programmed cell death). It is an essential and purposeful mechanism for the maintenance of normal bodily functions as worn, inefficient, unnecessary, and unhealthy cells are constantly disposed of and replaced by new ones. It is a delicate balancing act that all living beings take for granted. Too little apoptosis can lead to unregulated cell growth that can potentially lead to diseases such as cancer. On the other hand, too much apoptosis can lead to excessive cell death and tissue damage, which is what happens in the case of SCAs. The challenge for scientists such as Professor Chan is finding out what causes this to happen. ‘Despite tremendous scientific advances in our understanding of how our body functions, there is still much we do not know at the cellular and molecular level. There is much work that needs to be done to find out what triggers SCAs,’ he said.

Finding a Cure at the Molecular Level

With support from the Research Grants Council, the CUHK School of Life Sciences’ Biochemistry Programme and the Hong Kong Spinocerebellar Ataxia Association, Professor Chan and his team of collaborators from such diverse fields as biochemistry, genetics, cell biology, and neuroscience have been working diligently to answer the question using both experimental models, including fruit fly and mouse, and SCA patient cell samples. Their breakthrough came in 2008 when they discovered that certain toxic SCA RNA molecules disrupt the function of ‘ribosomes’, RNA/protein hybrids that are required for protein biosynthesis. Ribosomes are essential because they translate encoded DNA delivered by RNA, which provide instructions for ribosomes to combine individual amino acids to form proteins. There are tens of thousands of proteins in the body, each with their own structures and functions that regulate bodily functions.

More specifically, Professor Chan and his team found that the toxic RNA molecules prevent a protein named ‘nucleolin’ from binding with ‘chromatin’ inside the nucleolus, a special region in the cell nucleus responsible for producing ribosomes. This phenomenon is known as ‘nucleolar stress’ which eventually triggers excessive apoptosis in the cerebellum and leads to the development of SCAs.

The breakthrough findings have been published in the Proceedings of the National Academy of Sciences of the United States of America. In practical everyday terms, it means that scientists and clinicians are now in a better position to develop a cure for SCAs at the molecular level.

‘Now that we’ve identified the nucleolar stress signaling pathway, the next challenge is to explore whether it is possible to re-establish the supply of ribosomes in SCA patients. If we can do this, the damage to the cerebellum can be alleviated,’ said Professor Chan. Such a task will require more resources and collaborative research, considering that it was only a decade ago that scientists fully understood the molecular structure and functions of ribosomes.

Improving the Lives of SCA Sufferers

For a patient, there are few things worse than being told that one has a disease that is incurable. Hong Kong currently has about 300 patients with symptoms of SCAs with a third of them being confirmed cases. They face a life of constant therapy and neuropsychological rehabilitation, as well as an impaired quality of life. As a consultant of the Hong Kong Spinocerebellar Ataxia Association (HKSCAA), Professor Chan frequently sees the debilitating effects of SCAs with his own eyes. But he is optimistic about the prospects of finding a cure. ‘Working together with local experts including geneticists, neurologists, pathologists, radiologists, and the HKSCAA, we are currently in the process of establishing a SCA patient registry in Hong Kong. By curating essential pathological information of patients, we will soon be in a strong position to participate in clinical trials for SCAs from around the world. These activities will in a long run facilitate drug development and will also allow assessment of drug efficacy in the Chinese/Asian population.’