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Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring
Published on: June 23, 2015
Targeted rescue of a polycystic kidney disease mutation by lysosomal inhibition
Alexis Hofherr1, Claudius J Wagner2, Terry Watnick3
1Renal Division, Department of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal disease. The molecular pathogenesis of ADPKD is not completely known, and there is no approved therapy. To date, there is limited knowledge concerning the molecular consequences of specific disease-causing mutations. Here we show that the ADPKD missense variant TRPP2(D511V) greatly reduces TRPP2 protein stability, and that TRPP2(D511V) function can be rescued in vivo by small molecules targeting the TRPP2 degradation pathway. Expression of the TRPP2(D511V) protein was significantly reduced compared to wild-type TRPP2. Inhibition of lysosomal degradation of TRPP2(D511V) by the US Food and Drug Administration (FDA)-approved drug chloroquine strongly increased TRPP2 protein levels in vitro. The validation of these results in vivo requires appropriate animal models. However, there are currently no mouse models harboring human PKD2 missense mutations, and screening for chemical rescue of patient mutations in rodent models is time-consuming and expensive. Therefore, we developed a Drosophila melanogaster model expressing the ortholog of TRPP2(D511V) to test chemical rescue of mutant TRPP2 in vivo. Notably, chloroquine was sufficient to improve the phenotype of flies expressing mutant TRPP2. Thus, this proof-of-concept study highlights the potential of directed therapeutic approaches for ADPKD, and provides a rapid-throughput experimental model to screen PKD2 patient mutations and small molecules in vivo.
Insights
Autosomal dominant polycystic kidney disease (ADPKD) is linked to unstable TRPP2 protein. A new study shows chloroquine can stabilize this protein, offering a potential therapeutic strategy for ADPKD patients.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is the leading inherited cause of kidney failure.
- The precise molecular mechanisms underlying ADPKD, particularly the impact of specific mutations, remain incompletely understood.
- Currently, no targeted therapies exist for ADPKD.
Purpose of the Study:
- To investigate the molecular consequences of the TRPP2(D511V) missense variant associated with ADPKD.
- To identify potential therapeutic strategies for stabilizing mutant TRPP2 protein.
- To develop a rapid, in vivo model for screening ADPKD mutations and therapeutic compounds.
Main Methods:
- Characterized the stability of the TRPP2(D511V) mutant protein in vitro.
- Assessed the effect of chloroquine, an FDA-approved drug, on TRPP2(D511V) protein levels.
- Developed and utilized a Drosophila melanogaster model expressing the human TRPP2(D511V) ortholog to test in vivo rescue.
- Evaluated the phenotypic effects of chloroquine treatment in the Drosophila model.
Main Results:
- The ADPKD-associated TRPP2(D511V) variant significantly reduces TRPP2 protein stability.
- Chloroquine treatment effectively increased TRPP2(D511V) protein levels in vitro by inhibiting lysosomal degradation.
- Chloroquine administration ameliorated the disease phenotype in Drosophila expressing the mutant TRPP2 protein.
- The Drosophila model successfully demonstrated in vivo rescue of the mutant TRPP2 phenotype.
Conclusions:
- The TRPP2(D511V) mutation destabilizes the TRPP2 protein, contributing to ADPKD pathogenesis.
- Targeting the TRPP2 degradation pathway with small molecules like chloroquine shows therapeutic potential for ADPKD.
- The developed Drosophila model provides a valuable platform for high-throughput screening of ADPKD-causing mutations and therapeutic interventions.
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