LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice
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Le résumé fourni par la source
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset Parkinson's disease (PD), but the underlying pathophysiological mechanisms and the normal function of this large multidomain protein remain speculative. To address the role of this protein in vivo, we generated three different LRRK2 mutant mouse lines. Mice completely lacking the LRRK2 protein (knock-out, KO) showed an early-onset (age 6 weeks) marked increase in number and size of secondary lysosomes in kidney proximal tubule cells and lamellar bodies in lung type II cells. Mice expressing a LRRK2 kinase-dead (KD) mutant from the endogenous locus displayed similar early-onset pathophysiological changes in kidney but not lung. KD mutants had dramatically reduced full-length LRRK2 protein levels in the kidney and this genetic effect was mimicked pharmacologically in wild-type mice treated with a LRRK2-selective kinase inhibitor. Knock-in (KI) mice expressing the G2019S PD-associated mutation that increases LRRK2 kinase activity showed none of the LRRK2 protein level and histopathological changes observed in KD and KO mice. The autophagy marker LC3 remained unchanged but kidney mTOR and TCS2 protein levels decreased in KD and increased in KO and KI mice. Unexpectedly, KO and KI mice suffered from diastolic hypertension opposed to normal blood pressure in KD mice. Our findings demonstrate a role for LRRK2 in kidney and lung physiology and further show that LRRK2 kinase function affects LRRK2 protein steady-state levels thereby altering putative scaffold/GTPase activity. These novel aspects of peripheral LRRK2 biology critically impact ongoing attempts to develop LRRK2 selective kinase inhibitors as therapeutics for PD.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice
- Date Crossref
- 09/08/2011
- Éditeur
- Oxford University Press (OUP)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Novartis (Switzerland) pays non établi dans la noticeEntreprise
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Pathways Behavioral Services pays non établi dans la noticeOrganisation à but non lucratif
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Novartis Institutes for BioMedical Research Department of Neuroscience pays non établi dans la noticeStructure de recherche
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Preclinical Safety pays non établi dans la noticeÉtablissement de santé
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Department of Neuroscience pays non établi dans la noticeInstitution
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Global Discovery Chemistry pays non établi dans la noticeInstitution
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Department of Oncology pays non établi dans la noticeInstitution
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Developmental and Molecular Pathways and pays non établi dans la noticeInstitution
Novartis (Switzerland), Pathways Behavioral Services et Department of Neuroscience — Novartis Institutes for BioMedical Research, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.