Molecular Pathways Involved in LRRK2-Linked Parkinson’s Disease: A Systematic Review

Abstract

Parkinson’s disease is one of the most common neurodegenerative diseases affecting the ageing population, with a prevalence that has doubled over the last 30 years. As the mechanism of the disease is not fully elucidated, the current treatments are unable to effectively prevent neurodegeneration. Studies have found that mutations in Leucine-rich-repeat-kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD). Moreover, aberrant (higher) LRRK2 kinase activity has an influence in idiopathic PD as well. Hence, the aim of this review is to categorize and synthesize current information related to LRRK2-linked PD and present the factors associated with LRRK2 that can be targeted therapeutically. A systematic review was conducted using the databases PubMed, Medline, SCOPUS, SAGE, and Cochrane (January 2016 to July 2021). Search terms included “Parkinson’s disease”, “mechanism”, “LRRK2”, and synonyms in various combinations. The search yielded a total of 988 abstracts for initial review, 80 of which met the inclusion criteria. Here, we emphasize molecular mechanisms revealed in recent in vivo and in vitro studies. By consolidating the recent updates in the field of LRRK2-linked PD, researchers can further evaluate targets for therapeutic application.

How Parkinson’s Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types

“…The LRRK2 gene encodes the protein leucine-rich repeat kinase 2 (LRRK2), a large (288 kDa) multimeric protein in the Roco family [35,36]. LRRK2 has three protein-interactive domains towards its Nterminus: armadillo, ankyrin, and leucine-rich repeat motifs.…”

Structure of LRRK1 and mechanisms of autoinhibition and activation

“…Despite the molecular and cell biological similarities between LRRK1 and LRRK2, the proteins are strikingly different in their disease association. All the most common PD-linked mutations in LRRK2 are autosomal dominant gain-of-function mutations that activate its kinase 10 . LRRK2 has also been linked to Crohn's disease and leprosy 11,12 .…”

“…Our structural and mechanistic understanding of LRRK2 has expanded substantially over the past few years, with several structures of the protein now available [14][15][16][17] , along with insights into LRRK2's cellular localization 18 , substrates [6][7][8] and regulation 10 . This level of knowledge is missing for LRRK1, for which only low-resolution structures have been reported for the full-length protein 19 .…”

Structure of LRRK1 and mechanisms of autoinhibition and activation

“…While much is yet to be learned about LRRK2, our structural and mechanistic understanding of it has expanded significantly over the last few years, with several structures of the protein now available (Deniston et al, 2020;Myasnikov et al, 2021;Snead et al, 2022;Watanabe et al, 2020), along with insights into LRRK2's cellular localization (Usmani et al, 2021), substrates (Malik et al, 2021;Steger et al, 2017Steger et al, , 2016, and regulation (Ravinther et al, 2022). This level of knowledge is missing for LRRK1.…”

“…Despite the molecular and cell biological similarities between LRRK1 and LRRK2, the proteins are strikingly different when it comes to their disease association. LRRK2 is well known for its involvement in Parkinson’s Disease; all the most common PD-linked mutations in LRRK2 are autosomal dominant gain-of-function mutations that activate its kinase (Ravinther et al, 2022). LRRK2 has also been linked to Crohn’s disease and leprosy (Hui et al, 2018; Schurr and Gros, 2009).…”