In addition to the genetic mutations of
In addition to the genetic mutations of α-synuclein and LRRK2, an increasing body of evidence suggests that posttranslational modifications (PTMs) are also critically involved in PD pathogenesis [4,5] (Fig. 1). While PTMs serve to facilitate the normal functions of α-synuclein and LRRK2 in the healthy CCK-8 price [6,7], abnormal modifications may be associated with PD pathogenesis. Additionally, environmental toxicants such as rotenone, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and manganese (Mn) have been shown to interact with α-synuclein and LRRK2 and cause pathogenesis [8,9]. Mn is of particular interest since chronic exposure to Mn causes a neurological disorder resembling idiopathic PD, referred to as manganism . Although the underlying mechanisms of aberrant PTMs are not well understood, pathogenic modifications following environmental exposure are known to promote aggregation and oligomerization of α-synuclein  and abnormal increases in LRRK2 kinase activity .
Therefore, elucidating the mechanisms of PTMs that influence pathogenesis may greatly expand our understanding of PD and lead to the identification of therapeutic targets. This review will discuss the PTMs of α-synuclein and LRRK2, the impact of aberrant PTMs on PD pathogenesis and the influence of environmental toxicants on pathogenic modifications.
The interplay of α-synuclein and LRRK2 The genetic mutations of α-synuclein and LRRK2 in autosomal dominant PD have been extensively characterized , but their interplay in sporadic PD is not well understood. Lewy bodies, the pathogenic hallmark of PD, are comprised primarily of phosphorylated α-synuclein—though LRRK2 is often found accumulated within their core . This may indicate that beyond genetic mutations, aberrant PTMs of α-synuclein and LRRK2 may contribute to their pathogenicity. Despite their co-localization in Lewy bodies, few studies have found direct interactions between α-synuclein and LRRK2 under physiological conditions . In addition, α-synuclein and LRRK2 may interact indirectly through  their common pathways and functions. Both α-synuclein and LRRK2 complex with the 14-3-3 protein family after phosphorylation, a PTM contributing to the pathogenesis of both α-synuclein and LRRK2 [38,39]. α-synuclein and LRRK2 also modulate the dynamic cytoskeleton  and mediate vesicular transport , suggesting a common functionality that could be disrupted in PD pathogenesis. Although their interactions under physiological conditions are currently unknown, α-synuclein and LRRK2 have been co-immunoprecipitated in postmortem PD brain samples . It appears that LRRK2 regulates localization and clearance of α-synuclein in the brain via lysosomal degradation and microglial endocytosis [, , , , ]. G2019S LRRK2 mutation increases the formation of α-synuclein aggregates and exacerbates α-synuclein pathology , indicating that LRRK2 regulates the expression and proper clearance of α-synuclein. LRRK2 knockout attenuated α-synuclein aggregation in a transgenic mouse model as well as in vitro cell culture model . Interestingly, one study reported that knockdown of LRRK2 resulted in the aggregation of α-synuclein . This indicates that the interplay between LRRK2 and α-synuclein is complex and may be regulated by many factors. A recent study has shown that LRRK2 promoted α-synuclein aggregation by phosphorylating RAB35 , a RAB GTPase known to regulate vesicular trafficking and sorting . This relationship was observed in both in vitro and in vivo settings . Moreover, G2019S LRRK2 mutant kinase activity correlated with RAB35 hyperphosphorylation, resulting in α-synuclein aggregation, altered endosomal trafficking and lysosomal degradation in the brains of PD patients and in mice . Alternately, studies found that α-synuclein overexpression increased LRRK2 kinase activity, with concomitant dopaminergic neurodegeneration in mice , while inhibition of LRRK2 attenuated α-synuclein toxicity in rats [48,49].