Editorial: LRRK2-Fifteen Years From Cloning to the Clinic

In the time since the identification of LRRK2 at the PARK8 locus as the responsible gene mutated in a common autosomal dominantly inherited form of Parkinson's disease (Paisan-Ruiz et al., 2004; Zimprich et al., 2004), it has become increasingly evident that activity of this protein plays a crucial role in disease pathogenesis of Parkinson's disease (PD). Genetic variance within the LRRK2 gene gives rise to PD that generally overlaps clinically and neuropathologically with idiopathic PD (iPD). In the 15+ years since its isolation, we have gone from in-vitro assays and hypotheses, to state-of-the-art biomarkers and Phase I trials for treatments. There are various mechanisms proposed for LRRK2-mutant induced neuropathology in monogenic PD, however it remains unclear if these are the same mechanisms disrupted in iPD. Recent work has yielded two key findings: that LRRK2 activity may also play a major role in multiple forms of PD, not only those associated with mutations in the LRRK2 gene; and secondly, that this activity contributing to the neurodegeneration underlying PD occurs in both neuronal cells, as well as non-neuronal cells (e.g., microglia/macrophages, astrocytes, peripheral immune cells). This Research Topic provides a comprehensive collection of articles illustrating the role of LRRK2 in the physiology of neuronal and non-neuronal cells as well as the impacts of mutant LRRK2 in PD pathology, ranging from mechanisms, biomarkers and therapeutic opportunities. The articles provide a review of the literature as well as novel data around LRRK2 biochemical properties and cellular mechanisms in the context of endolysosomal system, synaptic function and immune-related pathways