Journal Article

DZNE-2026-00555

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Regulation between LRRK2 and PP2A signaling in cellular models of Parkinson's disease.

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

2026
Portland Press London

This record in other databases:    

Please use a persistent id in citations: doi:10.1042/BCJ20260194

Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of late-onset familial and idiopathic Parkinson's disease (PD), known to date. Importantly, recent data from postmortem 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 are still not completely understood. Accumulating evidence points to LRRK2 phosphoregulation, both autophosphorylation and phosphorylation by other kinases, as one potential molecular trigger of its activation. LRRK2 activation and localization are regulated by phosphatases such as protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A); however, the exact mechanism of this phosphoregulation is not known. Our data reveal that in vitro PP2A dephosphorylates sites within the RocCOR-GTPase domain of LRRK2 and, as a result, destabilizes 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 the PPP2CA-T304A mutant fails to do so, suggesting that impaired PP2A holoenzyme formation might be detrimental for LRRK2-PD.

Keyword(s): Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics (MeSH) ; Protein Phosphatase 2: metabolism (MeSH) ; Protein Phosphatase 2: genetics (MeSH) ; Humans (MeSH) ; Parkinson Disease: metabolism (MeSH) ; Parkinson Disease: genetics (MeSH) ; Parkinson Disease: pathology (MeSH) ; Parkinson Disease: enzymology (MeSH) ; Phosphorylation (MeSH) ; Signal Transduction (MeSH) ; HEK293 Cells (MeSH) ; Mutation (MeSH) ; Animals (MeSH) ; LRRK2 ; PP2A ; Parkinsons disease ; Phosphatase ; kinase ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; Protein Phosphatase 2 ; LRRK2 protein, human ; PPP2CA protein, human

Note: ISSN 1470-8728 not unique: **2 hits**.

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Contributing Institute(s):

1. Functional Neuroproteomics and Translational Biomarkers in Neurodegenerative Diseases (AG Gloeckner)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2026

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Database coverage:
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