LRRK2 regulates synaptic function through modulation of actin cytoskeletal dynamics

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, stemming from dopamine neuron loss.
• Synaptic dysfunction is increasingly recognized as an early event in PD pathogenesis, preceding overt neuronal loss.
• The precise mechanisms underlying early synaptic alterations in PD remain incompletely understood.

Purpose of the Study:

• To investigate the role of Leucine-rich repeat kinase 2 (LRRK2) in synaptic function and its relationship with brain-derived neurotrophic factor (BDNF) in Parkinson's disease.
• To elucidate the molecular pathways and cellular processes affected by LRRK2 dysfunction at the synapse.

Main Methods:

• Integration of literature meta-analysis, multi-omics data, biochemical assays, imaging, and electrophysiology.
• Utilized LRRK2 mouse models and human induced pluripotent stem cell (iPSC)-derived neurons lacking LRRK2.
• Investigated LRRK2 interactome, phospho-proteome, and BDNF signaling pathways.

Main Results:

• BDNF activates LRRK2, leading to the remodeling of the LRRK2 interactome towards actin cytoskeleton-related proteins.
• Gene-ontology analyses identified synapse-actin remodeling as a key pathway affected by LRRK2 activity.
• Loss of LRRK2 function impaired BDNF signaling, altered postsynaptic density, and affected synaptic activity regulation in human neurons.

Conclusions:

• LRRK2 plays a critical role in BDNF-dependent synaptic modulation.
• The synaptic actin cytoskeleton is a central hub for LRRK2-associated pathological processes in Parkinson's disease.
• These findings offer new insights into the early molecular mechanisms of PD and potential therapeutic targets.