Abstract:

Leucine-rich repeat kinase 2 (LRRK2), a gene linked to autosomal-dominantly inherited and sporadic Parkinson’s disease (PD) as a risk factor, encodes a large and complex protein with a dual enzymatic activity. LRRK2 contains several domains involved in protein-protein interactions, however, the presence of both a kinase and GTPase domain points to intracellular signaling functions (Marín, 2006). While LRRK2 has been linked to several molecular pathways important for neuronal activity, the observation that its expression is high in microglia has attracted the attention of different groups to understand whether LRRK2 dysfunctions in these cells may impact neuronal activity as secondary event. In this regard, since 2012 numerous studies have demonstrated that LRRK2 controls microglia activation and plays important roles in these cells. Microglia are highly specialized macrophages responsible for mediating innate immune defense in the brain and scavenging debris or misfolded/aggregated proteins. They are considered main actors upon an inflammatory stimulus, and although a well-regulated inflammatory response is crucial for tissue repair and brain homeostasis, an excessive and prolonged neuroinflammation can lead to overproduction of toxic molecules, which results in deleterious cellular damage, as observed in different neurodegenerative diseases including PD.