A regulatory loop regulating signaling between LRRK2 and PP2A in cellular models of Parkinsons disease

Athanasopoulos, P. S.; Memou, A.; Ho, F. Y.; Soliman, A.; Pots, H.; Papadopoulou, V.; von Zweydorf, F.; Sriraman, S.; Thouin, A. M.; Vandewynckel, L.; Sibran, W.; Chartier-Harlin, M.-C.; Nichols, R. J.; Greggio, E.; Taymans, J.-M.; Gloeckner, C. J.; Rideout, H. J.; Kortholt, A.

doi:10.1101/2025.10.07.680857

bioRxiv · 10.1101/2025.10.07.680857

A regulatory loop regulating signaling between LRRK2 and PP2A in cellular models of Parkinsons disease

Athanasopoulos, P. S.·Memou, A.·Ho, F. Y.·Soliman, A.·Pots, H.·Papadopoulou, V.·von Zweydorf, F.·Sriraman, S.·Thouin, A. M.·Vandewynckel, L.·Sibran, W.·Chartier-Harlin, M.-C.·Nichols, R. J.·Greggio, E.·Taymans, J.-M.·Gloeckner, C. J.·Rideout, H. J.·Kortholt, A.

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Abstract

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of late-onset familial and idiopathic Parkinsons disease (PD), known to date. Importantly, recent data from post-mortem tissue as well as biomarker studies suggest that independent of mutations, increased kinase activity of LRRK2 plays an essential role in idiopathic PD pathogenesis. Despite extensive research on LRRK2, its activation mechanism(s) and how the various mutations result in increased kinase activity and neuronal death is still not completely understood. Accumulating evidence points to LRRK2 phospho-regulation, both auto-phosphorylation and phosphorylation by other kinases, as one potential molecular trigger of its activation. LRRK2 activation and localization is regulated by phosphatases such as Protein phosphatase 1 (PP1) and Protein phosphatase 2A (PP2A), however the exact mechanism of this phospho-regulation is not known. Our data reveal that in vitro PP2A dephosphorylates sites within the RocCOR-GTPase domain of LRRK2 and as a result de-stabilizes LRRK2 dimers, with consequent reduction of its kinase activity. Strikingly, our data further highlight that LRRK2 in turn phosphorylates the catalytic subunit of the PP2A holoenzyme PPP2CA at its critical residue T304. Furthermore, LRRK2-mediated phosphorylation of PP2CA T304 alters the methylation of the C-terminus, which is crucial for both holoenzyme formation and catalytic activity. Importantly, expression of WT-PPP2CA protects from LRRK2-G2019S induced neuronal cell death, while PPP2CA-T304 mutants fail to do so, suggesting that impaired PP2A holoenzyme formation might be detrimental for LRRK2-PD.

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Athanasopoulos, P. S., Memou, A., Ho, F. Y., Soliman, A., Pots, H., Papadopoulou, V., von Zweydorf, F., Sriraman, S., Thouin, A. M., Vandewynckel, L., Sibran, W., Chartier-Harlin, M.-C., Nichols, R. J., Greggio, E., Taymans, J.-M., Gloeckner, C. J., Rideout, H. J., Kortholt, A.. 2025-10-07. A regulatory loop regulating signaling between LRRK2 and PP2A in cellular models of Parkinsons disease. https://doi.org/10.1101/2025.10.07.680857

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