Genetic Mutation in Familial Parkinson’s Traced to Its Target

Researchers have discovered the cellular role and target of the most common genetic cause of Parkinson’s disease: LRRK2 kinase mutations. The study, “Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases,” was published in eLife.

Parkinson’s disease is not generally considered a genetic disease, since most cases are idiopathic and only about 10 percent of all Parkinson’s cases have been linked to genetic causes. In this small subset, mutations in the LRRK2 gene are the greatest known genetic cause of familial PD, comprising 1 percent to 2 percent of all PD cases, according to the Michael J. Fox Foundation for Parkinson’s Research (MJFF). The prevalence of this genetic defect has led pharmaceutical companies to develop LRRK2 kinase inhibitors to correct the effects of these mutations. However, the lack of consensus regarding the physiological role and molecular substrates of LRRK2 has been an obstacle in the clinical development of such therapeutics.

Researchers from the Max Planck Institute of Biochemistry, the University of Dundee, MJFF, GlaxoSmithKline (GSK) and Merck have identified and validated the substrates in which the LRRK2 kinase directly exerts its activity. The team found that LRRK2 directly deactivates specific Rab proteins (3, 8, 10 and 12), and pathogenic LRRK2 variants increase this deactivation leading to deregulation of cellular trafficking. The researchers observed this process both in vivo and in vitro, using a series of models and techniques to validate the discovery, such as mice harbouring LRRK2 mutations, LRRK2 kinase inhibitors from GSK and Merck, and mass spectrometry for protein identification.

“Identification of Rab proteins as a LRRK2 substrate presents a tool to measure the impact of these inhibitors not only on LRRK2 levels but also on LRRK2 function. This critical component will advance development of these therapies to slow or stop Parkinson’s disease, patients’ greatest unmet need,” Marco Baptista, PhD, MJFF senior associate director of Research Programs, said in a press release.