Abstract
Mutations in LRRK2 are the most frequent cause of familial Parkinson’s disease (PD), with common LRRK2 non-coding variants also acting as risk factors for idiopathic PD. Currently, therapeutic agents targeting LRRK2 are undergoing advanced clinical trials in humans, however, it is important to understand the wider implications of LRRK2 targeted treatments given that LRRK2 is expressed in diverse tissues including the brain, kidney and lungs. This presents challenges to treatment in terms of effects on peripheral organ functioning, thus, protein interactors of LRRK2 could be targeted in lieu to optimize therapeutic effects. Herein an in-silico analysis of LRRK2 direct interactors in brain tissue from various brain regionswas conducted along with a comparative analysis of the LRRK2 interactome in the brain, kidney, and lung tissues. This was carried out based on curated protein–protein interaction (PPI) data from protein interaction databases such as HIPPIE, human gene/protein expression databases and Gene ontology (GO) enrichment analysis using Bingo. Seven targets (MAP2K6, MATK, MAPT, PAK6, SH3GL2, CDC42EP3 and CHGB) were found to be viable objectives for LRRK2 based investigations for PD that would have minimal impact on optimal functioning within peripheral organs. Specifically, MAPT, CHGB, PAK6, and SH3GL2 interacted with LRRK2 in the brain and kidney but not in lung tissue whilst LRRK2-MAP2K6 interacted only in the cerebellum and MATK-LRRK2 interaction was absent in kidney tissues. CDC42EP3 expression levels were low in brain tissues compared to kidney/lung. The results of this computational analysis suggest new avenues for experimental investigations towards LRRK2-targeted therapeutics.
Highlights
Parkinson’s disease (PD) is an age-related neurodegenerative disease affecting more than 1% of the population above 60 years with currently no curative therapies available (Tysnes and Storstein, 2017)
In 2004, point mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene were discovered by two groups simultaneously (Paisan-Ruíz et al, 2004; Zimprich et al, 2004) and subsequently, LRRK2 mutations have been linked to 5–8% of fa milial (Nichols et al, 2005) and 1–2% of sporadic PD cases (Gilks et al, 2005)
LRRK2 was queried for brain interactors with a high confidence score (>0.72) (Filter#1) in Human Integrated ProteinProtein Interaction rEference (HIPPIE)
Summary
Parkinson’s disease (PD) is an age-related neurodegenerative disease affecting more than 1% of the population above 60 years with currently no curative therapies available (Tysnes and Storstein, 2017). LRRK2 protein consists of ROC (Ras of complex proteins) GTPase domain, a COR (C-terminal of ROC) dimerization domain, and a kinase domain It consists of four tandem repeats domains N-terminal Armadillo, Ankyrin, Leucine-rich repeats, and a C-terminal WD40 fold (Marín, 2006). A recent study has shown that these kinase inhibitors have a reversible effect on the lung pheno type in non-human primates (Baptista et al, 2020) These exaggerated effects on peripheral organs might be because LRRK2 is ubiquitously expressed, with the highest expression levels observed in the kidney, lung, and monocytes. Drugs and treatments inhibiting LRRK2 to treat PD have been shown to induce pathologies in peripheral organs, the kidney and lungs (Herzig et al, 2011; Hinkle et al, 2012; Tong et al, 2010). Brain Research 1765 (2021) 147503 new avenues for LRRK2 targeted therapy with minimal off-target effects
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