The Parkinson’s Disease-Associated Protein Kinase LRRK2 Modulates Notch Signaling through the Endosomal Pathway


LRRK2 is linked to autosomal dominant late-onset Parkinson’s disease, suggesting that LRRK2 gain-of-function mutations lead to age-dependent degeneration of the midbrain dopaminergic neurons. In this study, we describe two novel LRRK2-associated proteins HERC2 and NEURL4, which are a ubiquitin ligase and an adaptor-like protein, respectively. HERC2 and NEURL4 direct LRRK2 to Notch signaling pathway, in which the LRRK2-NEURL4-HERC2 complex promotes the recycling of the Notch ligand Delta-like 1 (Dll1)/Delta (Dl) through the modulation of endosomal trafficking. As a result, the amounts of Dll1/D1 on the plasma membrane are increased, which affects negatively Notch signaling through cis-inhibition. The effect is enhanced by a Parkinson’s-disease associated mutation of LRRK2. Inhibition of Notch signaling in adult dopaminergic neurons impairs its functions and survival. These findings indicate a possible link between Notch pathway and Parkinson’s disease.


Vyšlo v časopise: The Parkinson’s Disease-Associated Protein Kinase LRRK2 Modulates Notch Signaling through the Endosomal Pathway. PLoS Genet 11(9): e32767. doi:10.1371/journal.pgen.1005503
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1005503

Souhrn

LRRK2 is linked to autosomal dominant late-onset Parkinson’s disease, suggesting that LRRK2 gain-of-function mutations lead to age-dependent degeneration of the midbrain dopaminergic neurons. In this study, we describe two novel LRRK2-associated proteins HERC2 and NEURL4, which are a ubiquitin ligase and an adaptor-like protein, respectively. HERC2 and NEURL4 direct LRRK2 to Notch signaling pathway, in which the LRRK2-NEURL4-HERC2 complex promotes the recycling of the Notch ligand Delta-like 1 (Dll1)/Delta (Dl) through the modulation of endosomal trafficking. As a result, the amounts of Dll1/D1 on the plasma membrane are increased, which affects negatively Notch signaling through cis-inhibition. The effect is enhanced by a Parkinson’s-disease associated mutation of LRRK2. Inhibition of Notch signaling in adult dopaminergic neurons impairs its functions and survival. These findings indicate a possible link between Notch pathway and Parkinson’s disease.


Zdroje

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