LRRK2 regulates synaptic function through modulation of actin cytoskeletal dynamics

Parkinson's disease (PD) is a disorder that impacts both motor and non-motor functions, primarily caused by the degeneration of dopamine-producing neurons in the brain. Emerging research indicates that dysfunction in synapses, the connections between neurons, can occur years before neuron loss is observed. However, the early stages of synaptic changes in PD are not yet fully understood.

In this study, researchers compiled data from various sources, including a meta-analysis of existing literature, multi-omics data, and direct experiments with Lrrk2 mouse models and human stem cell-derived neurons that lack the LRRK2 protein. Their findings reveal that the brain-derived neurotrophic factor (BDNF) interacts with LRRK2 in certain cell types, altering the network of proteins associated with the actin cytoskeleton.

This connection between BDNF and LRRK2 leads to changes in the structure and function of synapses. Additionally, the study shows that the absence of LRRK2 disrupts BDNF signaling, affecting the architecture of postsynaptic regions. Mice genetically engineered to lack Lrrk2 exhibit alterations in the structure of dendritic protrusions, although these changes diminish over time.

In human neuronal cells, the absence of LRRK2 impacts the maturation process and the way BDNF influences synaptic activity. The results collectively highlight the importance of LRRK2 in the regulation of synaptic function through its influence on the actin cytoskeleton, suggesting that this molecular player plays a central role in the pathophysiology of Parkinson's disease.