LRRK2 Regulates Dendritic Spine Dynamics and Synaptic Function through Interaction with the Postsynaptic Actin Cytoskeleton

Core Concepts

LRRK2 plays a critical role in regulating dendritic spine morphology and synaptic function in response to BDNF signaling by dynamically interacting with the postsynaptic actin cytoskeleton.

Abstract

The study investigates the role of the Parkinson's disease-associated kinase LRRK2 in regulating synaptic function and dendritic spine dynamics. Key findings:

BDNF stimulation rapidly increases LRRK2 phosphorylation at Ser935 in primary neurons and differentiated SH-SY5Y cells.

BDNF promotes the interaction of LRRK2 with an interconnected network of actin cytoskeleton-associated proteins, particularly those enriched at the postsynapse.

LRRK2 knockout neurons exhibit decreased BDNF-dependent spinogenesis and signaling through AKT and ERK1/2 pathways.

One-month old Lrrk2 knockout mice display defects in dendritic spine maturation, which disappear with age.

In human iPSC-derived cortical neurons, BDNF increases the frequency of miniature excitatory postsynaptic currents in wild-type but not in LRRK2 knockout neurons.

Phosphoproteomic analysis of Lrrk2 G2019S mutant synaptosomes reveals differential phosphorylation of proteins enriched in postsynaptic structural organization.

Together, these findings demonstrate a critical function of LRRK2 in BDNF-dependent synaptic processes and identify the postsynaptic actin cytoskeleton as a convergent site of LRRK2 pathophysiological activity.

Stats

BDNF treatment rapidly increases LRRK2 phosphorylation at Ser935 in primary mouse cortical neurons and differentiated SH-SY5Y cells.
LRRK2 knockout neurons exhibit decreased BDNF-induced phosphorylation of AKT and ERK1.
One-month old Lrrk2 knockout mice display shorter dendritic spine width and length compared to wild-type.
Phosphorylation of drebrin at Ser337/Ser339 is significantly reduced in Lrrk2 G2019S mutant synaptosomes.

Quotes

"BDNF treatment stimulates Ser935 phosphorylation of endogenous LRRK2 with a phosphorylation kinetics overlapping with that observed in primary neurons."
"LRRK2 knockout neurons exhibit decreased TrkB signaling and fail to induce BDNF-dependent spinogenesis."
"Lrrk2 knockout mice display defects in spine maturation, a phenotype that disappears with age."

Key Insights Distilled From

LRRK2 regulates synaptic function through BDNF signaling and actin cytoskeleton

by Tombesi,G., ... at www.biorxiv.org 11-01-2022

https://www.biorxiv.org/content/10.1101/2022.10.31.514622v3

Deeper Inquiries

How does the dynamic interaction between LRRK2 and the postsynaptic actin cytoskeleton regulate specific aspects of dendritic spine morphology and function

The dynamic interaction between LRRK2 and the postsynaptic actin cytoskeleton plays a crucial role in regulating specific aspects of dendritic spine morphology and function. LRRK2 is involved in BDNF-dependent synaptic processes, where it influences receptor traffic, spine morphology, and functionality in developing brains. Upon BDNF stimulation, LRRK2 undergoes phosphorylation at Ser935, leading to its relocalization to the actin cytoskeleton at the postsynaptic site. This interaction with actin-related proteins, such as drebrin, regulates actin dynamics in dendritic spines, promoting spine maturation and structural plasticity. The association of LRRK2 with actin cytoskeleton components increases upon BDNF stimulation, indicating a role for LRRK2 in actin-based dendritic spine remodeling. The modulation of LRRK2-actin interaction influences synaptic processes, including spinogenesis, neurotransmitter release, and synaptic transmission, highlighting the significance of this dynamic interplay in shaping dendritic spine morphology and function.

What are the potential compensatory mechanisms that rescue the developmental spine maturation defects observed in young Lrrk2 knockout mice

The rescue of developmental spine maturation defects observed in young Lrrk2 knockout mice may involve potential compensatory mechanisms that come into play as the animals age. One possible compensatory mechanism could be the involvement of LRRK1, the homologous kinase to LRRK2. Studies have suggested that LRRK1 may compensate for LRRK2 deficiency, as evidenced by the lack of overt neurodegeneration in single Lrrk2 KO mice. The expression patterns of LRRK1 and LRRK2 in the brain indicate a potential compensatory role, with LRRK1 possibly taking over some functions of LRRK2 during development. Additionally, other signaling pathways or proteins involved in dendritic spine maturation and synaptic plasticity may become upregulated or activated to compensate for the loss of LRRK2. These compensatory mechanisms could contribute to the rescue of spine maturation defects in aging Lrrk2 knockout mice, ensuring proper synaptic function and structural plasticity.

Could modulating the LRRK2-actin interaction be a therapeutic strategy to restore synaptic dysfunction in Parkinson's disease

Modulating the LRRK2-actin interaction could indeed be a promising therapeutic strategy to restore synaptic dysfunction in Parkinson's disease. Given the critical role of LRRK2 in BDNF-dependent synaptic processes and actin-dependent synaptic dynamics, targeting the interaction between LRRK2 and the postsynaptic actin cytoskeleton may offer a way to intervene in the synaptic abnormalities associated with PD. By influencing the actin dynamics in dendritic spines, modulating the LRRK2-actin interaction could potentially enhance spine maturation, synaptic plasticity, and neurotransmission. This approach could help restore proper synaptic function, mitigate synaptic damage, and potentially slow down the progression of PD-related neurodegeneration. Further research and drug development focusing on this specific interaction could lead to novel therapeutic interventions for PD targeting synaptic dysfunction.