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Acta Physiologica 2013; Volume 207, Supplement 694
92nd Annual Meeting of the German Physiological Society
3/2/2013-3/5/2013
Heidelberg, Germany
THE KINASE LRRK2, MUTATED IN PARKINSONS DISEASE, IS REQUIRED FOR VITAMIN D3 AND PHOSPHATE METABOLISM
Abstract number: O15
Mühlemann
1
R.
, Minder
1
N., Bettoni
1
C., Ruminska
1
J., Daryadel
1
A., Schnitzbauer
1
U., Kumar
1
M., Mohebbi
1
N., Biber
1
J., Hernando
1
N., Rovelli
2
G., Shimshek
2
D., van der Putten
2
H.,
Wagner
1
*C.
1
University of Zurich, Institute of Physiology, Zurich, Switzerland
2
Novartis Institutes for Biomedical Research, Basel, Switzerland
Mutations in the Leucine Rich Repeat Kinase (LRRK2, Park8) underlie about 5 % of familial and 1-2 % of sporadic cases of Parkinson disease (PD). LRRK2 is almost ubiquitously expressed with particularly high levels in kidney, lung, and brain. The role of LRRK2, its up- and downstream regulators and targets are unknown. Here we show in mice either lacking Lrrk2 or expressing the G2019S mutant (the most common mutation in PD patients) and in rats deficient for LRRK2 that phosphate metabolism is highly disturbed. The levels of PTH, FGF23, and 1,25OH2-vitamin D3 are altered in all three animal models. Renal phosphate excretion is increased in animals lacking Lrrk2 and decreased in G2019S mutants. Expression of the vitamin D receptor and the vitamin D activating and inactivating enzymes Cyp27b1 and Cyp24a1, as well as of klotho (coligand for FGF23) are altered in most organs expressing LRRK2. Changes in dietary phosphate intake in Lrrk2 WT and KO mice alter phosphate and vitamin D target genes in a LRRK2 dependent manner and application of vitamin D3 to wildtype mice increases LRRK2 expression. In vitro, inhibition of LRRK2 alters expression of Cyp24a1 and the intestinal phosphate transporter NaPiIIb. Our data suggest that LRRK2 plays a central role in regulating phosphate metabolism and hormones involved in its control.
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Acta Physiologica 2013; Volume 207, Supplement 694 :O15