PD-linked LRRK2 G2019S mutation impairs astrocyte morphology and synapse maintenance via ERM hyperphosphorylation

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Astrocytes play crucial roles in synapse formation and maintenance via perisynaptic processes.
• The LRRK2 G2019S mutation is a frequent cause of Parkinsonism.

Purpose of the Study:

• To investigate the impact of the LRRK2 G2019S mutation on astrocyte function and morphology.
• To identify the molecular mechanisms linking LRRK2 mutation to astrocyte dysfunction.

Main Methods:

• Analysis of ERM protein phosphorylation in astrocytes with LRRK2 G2019S mutation.
• Assessment of astrocyte morphology and excitatory synapse density.
• In vivo BioID proteomic analysis to identify Ezrin interactors.
• Investigation of the role of Atg7 in astrocyte morphology.

Main Results:

• LRRK2 G2019S mutation enhances ERM protein phosphorylation in a subset of cortical astrocytes.
• ERM hyperphosphorylation correlates with reduced astrocyte complexity and synapse density/function.
• Dampening ERM phosphorylation restores astrocyte morphology and synapse density.
• Astrocytic Ezrin interacts with autophagy regulator Atg7; this interaction is reduced by LRRK2 G2019S-induced phosphorylation.
• Atg7 is essential for maintaining astrocyte morphology.

Conclusions:

• The LRRK2 G2019S mutation alters astrocyte morphology and synaptic density through a pathway involving ERM proteins and the autophagy regulator Atg7.
• This effect is brain-region-specific, highlighting a novel mechanism in Parkinsonism pathogenesis.