A new approach to Parkinson's disease: inhibition of leucine-rich repeat kinase-2

Abstract

Background: Genetic studies have shown that mutations in several genes may be linked to Parkinson's disease including leucine-rich repeat kinase-2 (LRRK2). The most common of the LRRK2 mutants is the Gly2019Ser mutant.

Objective/methods: A paper suggesting that inhibitors of Gly2019Ser mutant may be useful in the treatment of Parkinson's disease associated with this mutant is evaluated.

Results: Overexpression of the wild-type LRRK2 or the Gly2019Ser LRRK2 mutant type produced cortical neuron injury in cell culture, and the mutant also caused cell death; this was reduced by GW5074. Administered intraperitoneally to mice, GW5074 prevented the loss of neurons induced by the Gly2019Ser LRRK2 mutant.

Conclusions: Selective Gly2019Ser LRRK2 mutant inhibitors may have potential in the treatment of Parkinsonism associated with mutations of this gene and GW5074 is a lead compound for this.

Keywords::

• cortical neurone injury
• GW5074
• LRRK2 mutants
• Parkinson's disease