Abstract
LRRK2 was identified in 2004 as the causative protein product of the Parkinson’s disease locus designated PARK8. In the decade since then, genetic studies have revealed at least 6 dominant mutations in LRRK2 linked to Parkinson’s disease, alongside one associated with cancer. It is now well established that coding changes in LRRK2 are one of the most common causes of Parkinson’s. Genome-wide association studies (GWAs) have, more recently, reported single nucleotide polymorphisms (SNPs) around the LRRK2 locus to be associated with risk of developing sporadic Parkinson’s disease and inflammatory bowel disorder. The functional research that has followed these genetic breakthroughs has generated an extensive literature regarding LRRK2 pathophysiology; however, there is still no consensus as to the biological function of LRRK2. To provide insight into the aspects of cell biology that are consistently related to LRRK2 activity, we analysed the plethora of candidate LRRK2 interactors available through the BioGRID and IntAct data repositories. We then performed GO terms enrichment for the LRRK2 interactome. We found that, in two different enrichment portals, the LRRK2 interactome was associated with terms referring to transport, cellular organization, vesicles and the cytoskeleton. We also verified that 21 of the LRRK2 interactors are genetically linked to risk for Parkinson’s disease or inflammatory bowel disorder. The implications of these findings are discussed, with particular regard to potential novel areas of investigation.
Highlights
Leucine Rich Repeat Kinase 2 (LRRK2) is the most frequently mutated gene in familial Parkinson’s disease (PD) (Paisan-Ruız et al, 2004; Zimprich et al, 2004), and has been identified as a risk locus for the sporadic form of the disease (Nalls et al, 2014)
The reasons for this volume of different and sometimes contradictory literature may be the result of variable reproducibility across the functional models available to study LRRK2; the not yet proven and sometimes axiomatic assumption that the physiological function of LRRK2 can be inferred via its pathology and vice versa; and the difficulties encountered studying an enzyme possessing two potentially independent activities that may link to independent cellular functions (Lewis & Manzoni, 2012)
In the light of these observations we propose the function of LRRK2 interactome to be associated with transport and trafficking, possibly regulating enzymatic events associated with cytoskeleton and vesicles
Summary
LRRK2 is the most frequently mutated gene in familial Parkinson’s disease (PD) (Paisan-Ruız et al, 2004; Zimprich et al, 2004), and has been identified as a risk locus for the sporadic form of the disease (Nalls et al, 2014). Many different functions have been reported to be associated with LRRK2, ranging from cytoskeleton organization to vesicle trafficking, from synaptic activities to autophagy, from mitochondria homeostasis to protein synthesis, involving multiple different signalling cascades such as the m-TOR and Wnt pathways (Paisan-Ruiz, Lewis & Singleton, 2013). None of these have been categorically proven; the only reproducible data at the moment appears to be the interaction between LRRK2 and 14-3-3 that has been shown to regulate LRRK2 localization in the cell (Dzamko et al, 2010). The reasons for this volume of different and sometimes contradictory literature may be the result of variable reproducibility across the functional models available to study LRRK2; the not yet proven and sometimes axiomatic assumption that the physiological function of LRRK2 can be inferred via its pathology and vice versa; and the difficulties encountered studying an enzyme possessing two potentially independent activities that may link to independent cellular functions (Lewis & Manzoni, 2012)
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