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HKUST Researchers Co-Discover a Novel Function of an Enzyme Offering Insight into the Pathology of Hereditary Spastic Paraplegia

A novel finding by the Hong Kong University of Science (HKUST) and Technology offers new insights into the pathology of Hereditary Spastic Paraplegia – a rare inherited disorder with symptoms of lower limb spasticity.

Researchers from HKUST and Institute of Biophysics, Chinese Academy of Science recently identified that an enzyme, atlastin (ATL) is used to regulate the transportation of proteins within cells.

Having found previous link to disease, the contribution to pathophysiology of ATL still remained unclear. A team led by Prof. Guo Yusong, Assistant Professor of Division of Life Science in the School of Science at HKUST, have discovered that deletion of ATL would drastically slow down the transportation of important proteins produced from within the cell to its surface, which could lead to malfunctioning of our physiology and normal bodily functions. The team also discovered that a mutant version of ATL can restore this function, providing insight for therapeutic potential. The finding was made in collaboration with Prof. Hu Junjie’s laboratory from the Institute of Biophysics of the Chinese Academy of Sciences.

Endoplasmic reticulum (ER) tubules are connected by dynamin-like GTPase atlastin (ATL). Using the latest CRISPR/Cas9 technology to deplete ATL, Prof Guo and his collaborators discovered that in ATL-deleted cells, not only do ER tubules became unconnected, but formation of COPII vesicles were also drastically reduced, affecting its protein packaging efficiency. In fact, many exit sites along the ER network failed to recruit COPII subunits, significantly slowing down the proteins’ movement. Further studies found both mobility of the proteins and COPII formation can be restored by a mutant version of ATL capable of tethering, but not fusing, ER tubules.

Prof. Guo said the findings offered new insights into how defects in ATL causes recessive hereditary spastic paraplegia. “Apparently, ATL-mediated membrane tethering plays a critical role in maintaining the necessary mobility of ER contents, while we are not the right parties to offer a therapeutic strategy, I hope our finding can help offer some clues to the search of a cure for the rare disease,” He said.

Prof. Guo is a leading expert on membrane trafficking. This research was funded by the Research Grants Council (RGC) of Hong Kong and the National Natural Science Foundation of China (NSFC). [APBN]