Regulation between LRRK2 and PP2A signaling in cellular models of Parkinsons disease - PubMed

3 days ago

LRRK2 mutations are a leading cause of late-onset familial and idiopathic Parkinson's disease, with increased kinase activity implicated even without mutations.
The activation mechanism of LRRK2, including how mutations increase kinase activity and lead to neuronal death, remains incompletely understood, but phospho-regulation is a potential trigger.
Phosphatases like PP1 and PP2A regulate LRRK2 activation and localization, though the exact mechanisms are not fully known.
In vitro, PP2A dephosphorylates sites in LRRK2's RocCOR-GTPase domain, destabilizing dimers and reducing kinase activity.
LRRK2 phosphorylates PP2A's catalytic subunit PPP2CA at T304, altering C-terminal methylation, which is crucial for holoenzyme formation and activity.
Expression of wild-type PPP2CA protects against LRRK2-G2019S-induced neuronal cell death, while T304 mutants do not, suggesting impaired PP2A holoenzyme formation may be detrimental in Parkinson's disease.

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