LRRK2; a dynamic regulator of cellular trafficking

Parkinson's disease (PD) represents the second most common neurodegenerative disorder, characterized clinically by bradykinesia, resting tremor, rigidity and postural instability, and a variety of non-motor features. The etiology of PD is unknown, however genetic, environmental and inflammatory factors may influence disease onset and progression. Genetic variability in leucine-rich repeat kinase 2 confers significant genotypic and population-attributable risk for LRRK2-parkinsonism that is clinically indistinguishable from idiopathic PD. Nevertheless, the age-associated midbrain pathology observed post-mortem in LRRK2-parkinsonism may involve the abnormal accumulation of either α-synuclein or tau, or just the loss of dopaminergic neurons and gliosis. While diverse biological functions have been described for this multi-domain protein in many cell types, evidence suggests LRRK2 may sense endosomal trafficking to orchestrate dynamic changes in vesicular flux and cytoskeletal architecture. This review posits the long-held belief that synaptic-axonal dysfunction and terminal degeneration may precede dopaminergic cell loss, and provocatively questions how facets of LRRK2 biology may influence this molecular pathogenesis.