
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2023.04.09.536178
preprint
2
Article
Astrocytic LRRK2 Controls Synaptic Connectivity via Regulation of ERM Phosphorylation
Wang Shiyi http://orcid.org/0000-0003-3433-3025

Baumert Ryan http://orcid.org/0000-0003-0487-4912

Séjourné Gabrielle http://orcid.org/0000-0002-4633-2700

Bindu Dhanesh Sivadasan http://orcid.org/0000-0002-1545-1547

Dimond Kylie
Sakers Kristina http://orcid.org/0000-0001-8853-053X

Vazquez Leslie http://orcid.org/0000-0002-5609-980X

Moore Jessica http://orcid.org/0000-0002-7577-7127

Tan Christabel Xin http://orcid.org/0000-0002-6483-5838

Takano Tetsuya http://orcid.org/0000-0002-2599-3155

Rodriguez Maria Pia http://orcid.org/0000-0003-0949-3326

Soderling Scott H. http://orcid.org/0000-0001-7808-197X

La Spada Albert R. http://orcid.org/0000-0001-6151-2964

Eroglu Cagla http://orcid.org/0000-0002-7204-0218

28 8 2024
2023.04.09.536178https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
http://biorxiv.org/lookup/doi/10.1101/2023.04.09.536178
nihpp-2023.04.09.536178.pdf
SUMMARY

Astrocytes, a major glial cell type of the brain, regulate synapse numbers and function. However, whether astrocyte dysfunction can cause synaptic pathologies in neurological disorders such as Parkinson’s Disease (PD) is unknown. Here, we investigated the impact of the most common PD-linked mutation in the leucine-rich repeat kinase 2 ( LRRK2 ) gene (G2019S) on the synaptic functions of astrocytes. We found that both in human and mouse cortex, the LRRK2 G2019S mutation causes astrocyte morphology deficits and enhances the phosphorylation of the ERM proteins (Ezrin, Radixin, and Moesin), which are important components of perisynaptic astrocyte processes. Reducing ERM phosphorylation in LRRK2 G2019S mouse astrocytes restored astrocyte morphology and corrected excitatory synaptic deficits. Using an in vivo BioID proteomic approach, we found Ezrin, the most abundant astrocytic ERM protein, interacts with the Autophagy-Related 7 (Atg7), a master regulator of catabolic processes. The Ezrin/Atg7 interaction is inhibited by Ezrin phosphorylation, thus diminished in the LRRK2 G2019S astrocytes. Importantly, Atg7 function is required to maintain proper astrocyte morphology. These studies reveal an astrocytic molecular mechanism that could serve as a therapeutic target in PD.
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pmc
