Perspective on the current state of the LRRK2 field

Abstract

Almost 2 decades after linking LRRK2 to Parkinson's disease, a vibrant research field has developed around the study of this gene and its protein product. Recent studies have begun to elucidate molecular structures of LRRK2 and its complexes, and our understanding of LRRK2 has continued to grow, affirming decisions made years ago to therapeutically target this enzyme for PD. Markers of LRRK2 activity, with potential to monitor disease progression or treatment efficacy, are also under development. Interestingly, there is a growing understanding of the role of LRRK2 outside of the central nervous system in peripheral tissues such as gut and immune cells that may also contribute to LRRK2 mediated pathology. In this perspective, our goal is to take stock of LRRK2 research by discussing the current state of knowledge and critical open questions in the field.

Fig. 1. Timeline of key milestones in the advancement of the field of LRRK2 research.

Numbers next to the stars (*) denote the citation references pertaining to the milestone. #See text above for the ClinicalTrials.gov identifiers (NCT numbers) for the clinical milestones. §https://investors.biogen.com/news-releases/news-release-details/biogen-and-denali-collaborate-lrrk2-program-parkinsons-disease.

Fig. 2. Schematic of the LRRK2 domain structure.

Above the schematic, key amino acid substitutions are indicated that alter risk for PD, including mutations that increase risk for PD such as pathogenic mutations (red) and risk factor mutations (blue) as well as mutations that confer reduced risk for PD (green). Phosphorylated residues are given below the schematic, with heterologous phosphosites give in blue and autophosphorylation sites in red. Figure adapted from ref. .