Two counteracting proteins and their implications for Machado-Joseph Disease

13 October 2021

Scientists have discovered an intricate relationship between two proteins in our nerve cells that uncover new insights into neurodegenerative disorders such as Machado-Joseph Disease (MJD).

MJD, also known as spinocerebellar ataxia type 3 (SCA3), is a rare and inherited condition in which patients lack muscular control. Problems include difficulty with gait and balance, double vision, and symptoms similar to Parkinson's disease, with patients eventually declining into a bedridden state.

In collaboration with the University of Oxford, Professor Edwin Chan (Croucher Scholarship 1996) and his team from the School of Life Sciences at the Chinese University of Hong Kong (CUHK) have discovered that two proteins, Prpf19 and Exoc 7, play an important role in understanding MJD.

In their research published in Cell Death & Disease, Chan and researchers discovered that Prpf19 alleviated the toxicity of SCA3 cells, the disease protein for MJD, through a process called ubiquitin-proteasome degradation. They noticed improvements in animal models with SCA3 disease when Prpf19 was present.

However, the team also uncovered the important role of Exoc 7, a Prpf19-associated partner protein that controls trafficking of proteins within cells. They found that Exoc7’s coiled-coil domain, which is a special region of the protein, actually restrains the functioning of Prpf19.

In addition, the researchers found that Exoc7 shuttles to the cell nucleus, where it binds directly to Prpf19 and interferes with pre-mRNA splicing, causing Prpf19 to lose its beneficial effect on MJD disease models.

“The current study demonstrates an intricate relationship between Prpf19 and Exoc7, two crucial proteins in nerve cells,” Chan said. “Elucidating the mechanism [for the] action of protein networks that govern protein aggregation will allow us to develop potential small molecules or activators targeting Prpf19, with the hope of providing novel strategies for curing MJD and other neurodegenerative disorders.

Chan hopes these findings will provide important insight into rare disease translational biomedicine research.

Edwin Chan Ho-yin is Professor and Associate Director of the Biochemistry Programme at the School of Life Sciences, Chinese University of Hong Kong (CUHK), among other roles at the university. Chan received his undergraduate training in biochemistry at CUHK. He undertook doctoral studies in genetics at the University of Cambridge, UK, and postdoctoral research in neuroscience at the University of Pennsylvania, US. He has been investigating rare neurological and neuromuscular disorders for over 20 years. In 2014, he established an intercontinental research collaboration network on rare neuronal diseases, including amyotrophic lateral sclerosis/frontotemporal dementia, Huntington’s disease, myotonic dystrophy, and spinocerebellar ataxias. Chan was awarded a Croucher Scholarship in 1996.

To view Professor Chan’s Croucher profile, please click here.