At the Crossroads of Synapses and Signaling: The Role of LRRK2 in Neuronal Communication
TL;DR
How LRRK2-dependent trafficking mechanisms regulate key components of synaptic transmission, including glutamatergic and GABAergic receptors, as well as astrocytic transporters are examined, highlighting how disruption of these processes affects neurotransmitter clearance, receptor activation, and ultimately E/I balance.
Abstract
Precise control of membrane protein localization and turnover is essential for synaptic function and circuit stability. Disruption of these processes alters the surface expression of receptors and transporters, ultimately impacting the excitatory/inhibitory (E/I) balance. Leucine-rich repeat kinase 2 (LRRK2) is emerging as a key regulator of these membrane-associated processes, acting at the interface between intracellular trafficking and synaptic signaling. LRRK2 integrates kinase activity with scaffolding functions to coordinate Rab-dependent vesicular trafficking, endosomal recycling, cytoskeletal dynamics, and endolysosomal pathways. Through these mechanisms, it controls the surface expression and distribution of synaptic receptors and neurotransmitter transporters in both neuronal and glial compartments. Pathogenic LRRK2 variants associated with Parkinson’s disease (PD), converge on kinase hyperactivation and lead to sustained alterations in trafficking networks, resulting in selective mislocalization of membrane proteins. In this review, we examine how LRRK2-dependent trafficking mechanisms regulate key components of synaptic transmission, including glutamatergic and GABAergic receptors, as well as astrocytic transporters. We highlight how disruption of these processes affects neurotransmitter clearance, receptor activation, and ultimately E/I balance. Notably, accumulating evidence indicates that LRRK2 functions as an upstream coordinator of membrane organization at the crossroads of synaptic signaling and neurotransmitter homeostasis. Understanding how LRRK2 regulates trafficking pathways across cellular compartments provides mechanistic insight into circuit vulnerability in PD and highlights membrane-targeted strategies as potential approaches for restoring synaptic stability. Graphical Abstract LRRK2 in Synaptic Communication. LRRK2 acts as a central regulator of membrane trafficking in neurons and astrocytes. Through control of vesicular pathways, cytoskeletal dynamics, and endolysosomal function, LRRK2 modulates synaptic receptors and neurotransmitter transporters, contributing to excitatory/inhibitory balance. Pathogenic variants disrupt these processes, promoting synaptic dysfunction and circuit instability