LRRK2 and the fragile synapse: a molecular prelude to Parkinson's disease?

Parkinson's disease (PD) is a multisystem disorder presenting motor and non-motor symptoms. Motor dysfunction is the most debilitating, caused by the degeneration of dopamine-producing neurons. Increasing evidence indicates that synapse demise occurs years before neuronal death. Yet, the early synaptic dysfunc- tions in PD remain poorly understood. Leucine-Rich Repeat Kinase 2 (LRRK2), a serine/threonine kinase and GTPase relevant for both familial and sporadic forms of PD, has been increasingly associated with synaptic processes. These include the phosphorylation of key synaptic proteins and interactions with cytoskeletal components. Brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) are fundamental for synapse maturation, maintenance, and plasticity. Recent findings indicate that neurotrophic signaling is impaired in PD. In this review, we critically discuss the significance of identifying and clarifying the early molecular events leading to synaptic dysfunction in PD. We examine how mutant LRRK2 affects these processes and the relationship between LRRK2 and BDNF signaling from both mechanistic and therapeutic perspectives.