New Parkinson’s Target Discovered on a Lark

Cytoscape network analysis of Rab8a interacting proteins determined by Steger et al. eLife 2016;5:e12813. DOI: 10.7554

The latest “lark” research was not by an ornithologist studying birds, rather by a group of Parkinson’s disease researchers investigating the Park8 gene, which encodes the protein, leucine-rich repeat kinase-2 (LRRK2, pronounced “lark 2”), which has been identified as a susceptibility gene in both familial and non-familial Parkinson’s disease. Parkinson’s, a chronic, progressive, and debilitating neurological disorder, is the second most common neurodegenerative disorder among the elderly. Many studies have revealed multiple genetic and environmental factors contributing to the development of Parkinson’s disease. While LRRK2 has been implicated in a variety of cellular processes, the exact mechanisms of its actions, and more importantly its targets, have not been identified.

In a study published in eLife in January, Matthias Mann at the Max Planck Institute of Biochemistry in Martinsreid and colleagues in a multi-center, collaborative project sought to identify the physiological targets of LRRK2. Using state-of-the-art mass spectrometry analysis to identify potential LRRK2 targets, they found a single class of proteins: the small GTPase family of Rabs, essential molecules in the intracellular highway. The different Parkinson’s disease-associated mutations in the LRRK2 protein result in increased Rab phosphorylation at a specific site that the researchers believed may impact Rab functions. Mann and colleagues showed that regulation of Rabs by LRRK2 led to fewer interactions with Rab-associated proteins and altered signaling by these proteins.

Kinases, like LRRK2, are appealing targets for drug development as they are central in cell signaling and have been extensively studied, which allows the design of specific, targeted drugs with minimal side-effects. Now Rabs can be used as a read-out for the effectiveness of LRRK2-targeting drugs. Furthermore, this study supports previous association of Rab proteins with Parkinson’s disease and adds context to that role, and the many years of research on Rabs can now be linked to a better understanding of the disease.