MJFF Backs Investigation of Parkinson’s-linked Protein Complex

A project investigating a complex formed by two key proteins involved in Parkinson’s disease development has received nearly $150,000 in funding from the Michael J. Fox Foundation for Parkinson’s Research (MJFF).

The research team behind the project believes the interaction between these two proteins — LIMP-2 and GCase — may be a basis for developing new therapies for the disease, according to a university press release.

The one-year grant totaling $149, 500 will support the research to further analyze the structures of LIMP-2 and GCase, better understand how they interact and form a protein complex, and identify what role that complex plays in Parkinson’s disease. 

The project, titled “LIMP-2 as a Scaffolding Protein to Characterize PD-Associated GCase Variants,” is led by Friederike Zunke, PhD, an assistant professor at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany, and Philipp Arnold, PhD, a senior post-doctoral fellow at FAU’s Institute of Anatomy. 

The GBA gene provides instructions for making the enzyme GCase (beta-glucocerebrosidase), which is vital for the function of lysosomes, a cellular structure that breaks down and recycles cell waste. Mutations in GBA can impair GCase function, leading to a toxic accumulation of waste in the cell and subsequent inflammation. About 7–12% of all Parkinson’s disease patients have a GBA mutation.

“Activators for GCase are promising candidates for clinical intervention in Parkinson’s patients. Some activators for GCase are in clinical trials right now,” the researchers wrote.

The newly-funded project builds on their prior research, funded by MJFF in 2018, which explored the structure of the GCase and LIMP-2 complex. They found that the two proteins bind together and LIMP-2 acts as a transporter as the proteins travel to the lysosome. 

“In previous work, we found that LIMP-2 can increase GCase activity. After determining the structure of this protein complex we want to utilize the contact site for the design of a GCase activator,” the researchers wrote.

Zunke and Arnold are developing an artificial model of the GCase-LIMP-2 protein complex, based on a preliminary structure identified in their previous study, which will be used to replicate and investigate the interaction between the two proteins. The team will attempt to use LIMP-2 as a tool to harvest GCase in cell cultures and test the properties of this protein complex.

The project also will include GCase mutations that are linked to Parkinson’s, since these can “eventually shed light on how the mutations influence complex stability and thereby enzymatic activity of GCase,” the researchers wrote.