Molecular mechanisms defining penetrance of LRRK2-associated Parkinson's disease

Abstract

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of dominantly inherited Parkinson's disease (PD). LRRK2 mutations, among which p.G2019S is the most frequent, are inherited with reduced penetrance. Interestingly, the disease risk associated with LRRK2 G2019S can vary dramatically depending on the ethnic background of the carrier. While this would suggest a genetic component in the definition of LRRK2-PD penetrance, only few variants have been shown to modify the age at onset of patients harbouring LRRK2 mutations, and the exact cellular pathways controlling the transition from a healthy to a diseased state currently remain elusive. In light of this knowledge gap, recent studies also explored environmental and lifestyle factors as potential modifiers of LRRK2-PD. In this article, we (i) describe the clinical characteristics of LRRK2 mutation carriers, (ii) review known genes linked to LRRK2-PD onset and (iii) summarize the cellular functions of LRRK2 with particular emphasis on potential penetrance-related molecular mechanisms. This section covers LRRK2's involvement in Rab GTPase and immune signalling as well as in the regulation of mitochondrial homeostasis and dynamics. Additionally, we explored the literature with regard to (iv) lifestyle and (v) environmental factors that may influence the penetrance of LRRK2 mutations, with a view towards further exposomics studies. Finally, based on this comprehensive overview, we propose potential future in vivo, in vitro and in silico studies that could provide a better understanding of the processes triggering PD in individuals with LRRK2 mutations.

Keywords: LRRK2; Parkinson’s disease; Rab signalling; environment; genetic modifiers; mitochondria; penetrance; toxin exposure.

Figure 1

Scheme summarizing the levels of impact of genetic and non-genetic modifiers on the penetrance of mutations in Leucine-rich repeat kinase 2 (LRRK2). The most frequent mutation in LRRK2, G2019S, is situated in the kinase domain of the protein. Enhanced kinase activity due to G2019S increases the phosphorylation of a subgroup of Rab GTPases that were identified as substrates of LRRK2. Via Rabs, LRRK2 acts on cellular functions such as lysosomal degradation and vesicular trafficking, which in turn may interfere with mitochondrial homeostasis and dynamics as well as immune signalling. How these molecular mechanisms control the transition of an LRRK2 G2019S mutation carrier from healthy to diseased currently remains elusive. Nonetheless, significant efforts are being made to develop and advance LRRK2 small molecule inhibitors into clinical trials as kinase inhibition is thought to slow the advancement of the movement disorder. Scheme adapted from Alessi and Sammler (2018) [43]. The figure was created using BioRender.com.

Figure 2

LRRK2 gene expression in single cells from postmortem midbrain of idiopathic Parkinson’s disease (PD) patients and aged controls. We extracted LRRK2 expression data from our previously generated single-nuclei RNA sequencing atlas of the human midbrain that is available on GEO under the accession number GSE157783 [65]. This analysis revealed highest levels of LRRK2 in microglia and oligodendrocyte progenitor cells (OPCs). Comparison of the LRRK2 mRNA abundance in these two cell types derived from IPD patients and controls revealed a disease-specific upregulation only in microglia.