Abstract
Leucine-rich repeat kinase 2 (LRRK2) is genetically implicated in both familial and sporadic Parkinson's disease (PD). Moreover, LRRK2 has emerged as a compelling therapeutic target for the treatment of PD. Consequently, there is much interest in understanding LRRK2 and its role in PD pathogenesis. LRRK2 is constitutively phosphorylated on two serines, S910 and S935, that are required for interaction of LRRK2 with members of the 14-3-3 family of scaffolding proteins. Pathogenic LRRK2 missense mutations impair the phosphorylation of LRRK2 at these sites, but whether this contributes to PD pathology is unclear. To better understand how loss of LRRK2 phosphorylation relates to PD pathology, we have studied double knockin mice in which Lrrk2's serine 910 and 935 have both been mutated to alanine and can therefore no longer be phosphorylated. Nigrostriatal PD pathology was assessed in adult mice, aged mice, and mice inoculated with α-synuclein fibrils. Under all paradigms there was evidence of early PD pathology in the striatum of the knockin mice, namely alterations in dopamine regulating proteins and accumulation of α-synuclein. Striatal pathology was accompanied by a significant decrease in the number of astrocytes in the knockin mice. Despite striatal pathology, there was no degeneration of dopamine neurons in the substantia nigra and no evidence of a PD motor phenotype in the knockin mice. Our results suggest that modulation of LRRK2 serine 910 and 935 phosphorylation sites may have implications for dopamine turnover and astrocyte function, but loss of phosphorylation at these residues is not sufficient to induce PD neurodegeneration.
Highlights
Genetic and clinical evidence suggest a pathogenic role for leucinerich repeat kinase 2 (LRRK2) in both sporadic and familial Parkinson's disease (PD) (Healy et al, 2008; Nalls et al, 2014; Paisan-Ruiz et al, 2004; Zimprich et al, 2004)
As knockout of Lrrk2 in kidney has previously been associated with morphological changes (Tong et al, 2010), we examined kidney appearance and weight in the KI mice, but found no difference compared to wild type
Mouse embryonic fibroblasts (MEFs) derived from the KI mice show similar levels of total Lrrk2 and in vitro kinase activity compared to wild type MEFs, phosphorylation of the Lrrk2 substrate Rab10 (Steger et al, 2016) was markedly reduced in KI MEFs when assessed by phos-tag assay (Ito et al, 2016)
Summary
Genetic and clinical evidence suggest a pathogenic role for leucinerich repeat kinase 2 (LRRK2) in both sporadic and familial Parkinson's disease (PD) (Healy et al, 2008; Nalls et al, 2014; Paisan-Ruiz et al, 2004; Zimprich et al, 2004). Six out of the seven 14-3-3 isoforms interact with LRRK2 in a manner dependent on the phosphorylation of LRRK2 at serine (S) 910 and S935, two residues found just prior to the proteins leucine-rich repeat domain (Nichols et al, 2010; Stevers et al, 2017). In overexpressing cell culture models, ablation of S910 and S935 phosphorylation via mutation of these residues to alanine, results in the loss of 14-3-3 binding and the accumulation of LRRK2 in the cytoplasm (Nichols et al, 2010). This suggests a role for S910 and S935 phosphorylation in the regulation of LRRK2's subcellular localization
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