Targeting LRRK2 in Parkinson’s disease: an update on recent developments

ABSTRACT

Introduction: LRRK2 research has progressed significantly in recent years with more reports of LRRK2 interactors and the development of more specific and sophisticated LRRK2 kinase inhibitors. Identification of bone fide LRRK2 substrates will provide new therapeutic targets in LRRK2-linked Parkinson’s disease (PD).

Areas covered: This review aims to put current LRRK2 research into perspective. Beginning with recent LRRK2 mammalian models employed for in vivo validation of LRRK2 substrates, followed by updates on reported LRRK2 interactors and their inferred mechanisms. Finally an overview of commonly used LRRK2 kinase inhibitors will be depicted.

Expert opinion: Identification of LRRK2 non-kinase functions suggests the possibility of alternative LRRK2 drug target sites and these should be further explored. Studies on the effects of LRRK2 kinase inhibition on its non-kinase function and its self-regulatory role will provide further insights on its pathophysiologic mechanisms. Development of robust measurements of LRRK2 inhibitor efficacy will be required. These would include identification of specific imaging ligands or direct biochemical assays that can accurately capture its intrinsic activity. Testing of new therapeutic drug targets in both LRRK2 carriers and non LRRK2-linked patients will be important since their phenotype is similar.

KEYWORDS:

• Parkinson’s disease
• LRRK2
• inhibitors

Article Highlights

• Serine935 appears to be the main LRRK2 phospho site used as an indication of its kinase activity.

• LRRK2 mammalian models (rodents and iPSCs) that are useful for pre-clinical testing will be discussed.

• An update on current LRRK2 substrates and their implicated mechanisms in autophagy, Rab GTPases, mitochondria and cytoskeletal dynamics.

• An overview depicting the validation and limitations of LRRK2 pharmacological kinase inhibitors commonly used to elucidate LRRK2 function.

• Summary of take home messages

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The authors are supported by the National Medical Research Council (STaR investigator and PD Translational Clinical Research program grants).