Mutations in the enzyme β-glucocerebrosidase (GCASE) can increase the likelihood of developing Parkinson’s disease up to twentyfold and are also implicated in a rare metabolic disorder. A research team led by Prof. dr. Friederike Zunke and PD Dr. Philipp Arnold, along with collaborators from Osnabrück, Belgium, and the USA, have successfully visualized the structure of the GCASE enzyme in conjunction with its transport protein LIMP-2 using cryo-electron microscopy.

GCASE Structure as a Risk Factor

The absence or malfunction of the GCASE enzyme poses meaningful health challenges. “An enzyme is a protein with a very specific task in the body,” explains Prof. Zunke, deputy head of the molecular neurological department (Head: Prof. Dr. Jürgen Winkler) of the University Hospital Erlangen.”in the case of the GCASE, this enzyme is responsible for the breakdown of its specific substrate, which is a lipid, so to speak, a fat.” when GCASE fails to break down its substrate, the accumulation of undigested lipids and othre protein units becomes problematic, especially in cells that do not divide.

Prof. Zunke adds, “If a cell shares itself, its content is also shared. If I have a protein aggregate, i.e. a protein lump in the cell, it would divide together with the cell and then the problem would probably be less serious. Though, our nerve cells no longer share and thus notably protein aggregates accumulate ther, the enzyme should not work.”

“That is why the preservation of the enzymatic activity of GCASE is an critically important building block when researching new therapy options for Parkinson’s disease,”

This process is central to Gaucher’s disease, a lysosomal storage disorder. Lysosomes, membrane-enclosed cell organelles, contain enzymes that break down foreign substances and cellular waste, functioning as the cell’s recycling system. In Gaucher’s disease, lysosomes become clogged with the GCASE substrate, leading to an accumulation of waste and eventual cell death.

GCASE is also a major genetic risk factor for parkinson’s disease.Certain GCASE mutations can increase the risk of developing Parkinson’s up to twenty times. “That is why the preservation of the enzymatic activity of GCASE is an important building block when researching new therapy options for parkinson’s disease,” explains Friederike Zunke. Studies indicate that activating the GCASE enzyme reduces the accumulation of cell-damaging aggregates.

“This principle has been tested for various activators in clinical studies. But it has also been shown how critically important a detailed understanding of the structure of this protein and its van is,” says Philipp Arnold from the Institute for Functional and Clinical anatomy (Director: Prof. Dr. HC Mult. Friedrich Paulsen) of the FAU.

Exploring new Therapeutic Avenues

The research team, including Friederike Zunke and Philipp Arnold, has not only visualized the GCASE molecule but also elucidated the interaction between the enzyme and its transport protein, LIMP-2. “We have seen that the enzyme is activated solely by binding to its transporter LIMP-2.In the future, against the background of the now dissolved structure of the transport complex, it could be activated to design new therapeutic agents that are right there to protein,” explains Friederike Zunke. Further research is underway.