The Mystery of 'Little Brain' Deterioration

September 2012

Spinocerebellar ataxias (SCAs) is a group of genetic 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. Prof. Chan Ho-yin Edwin in the CUHK School of Life Sciences and his research team have unveiled that the failure of RNA (Ribonucleic acid), a form of nucleic acid that has the essential roles of transmitting genetic information contained in DNA (Deoxyribonucleic acid) and to synthesize proteins, to transmit genetic code properly is a cause of this incurable disease.

His 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.

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 (i.e., programmed cell death) in the cerebellum and leads to the development of SCAs.

'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.

Professor Chan has dedicated himself to the study and research on the pathogenic pathways of SCAs in the hope of finding the causes of SCA.