Targeted rescue of a polycystic kidney disease mutation by lysosomal inhibition.
Identifieur interne : 000D55 ( Main/Exploration ); précédent : 000D54; suivant : 000D56Targeted rescue of a polycystic kidney disease mutation by lysosomal inhibition.
Auteurs : Alexis Hofherr [Allemagne] ; Claudius J. Wagner [Allemagne] ; Terry Watnick [États-Unis] ; Michael Köttgen [Allemagne]Source :
- Kidney international [ 1523-1755 ] ; 2016.
Descripteurs français
- KwdFr :
- Animaux, Antirhumatismaux (pharmacologie), Antirhumatismaux (usage thérapeutique), Canaux cationiques TRPP (génétique), Canaux cationiques TRPP (métabolisme), Cellules HEK293, Cellules HeLa, Chloroquine (pharmacologie), Chloroquine (usage thérapeutique), Drosophila melanogaster, Femelle, Humains, Lysosomes (), Lysosomes (métabolisme), Mutation faux-sens, Mâle, Polykystose rénale autosomique dominante (génétique), Polykystose rénale autosomique dominante (métabolisme), Polykystose rénale autosomique dominante (traitement médicamenteux), Stabilité protéique, Évaluation préclinique de médicament.
- MESH :
- génétique : Canaux cationiques TRPP, Polykystose rénale autosomique dominante.
- métabolisme : Canaux cationiques TRPP, Lysosomes, Polykystose rénale autosomique dominante.
- pharmacologie : Antirhumatismaux, Chloroquine.
- traitement médicamenteux : Polykystose rénale autosomique dominante.
- usage thérapeutique : Antirhumatismaux, Chloroquine.
- Animaux, Cellules HEK293, Cellules HeLa, Drosophila melanogaster, Femelle, Humains, Lysosomes, Mutation faux-sens, Mâle, Stabilité protéique, Évaluation préclinique de médicament.
English descriptors
- KwdEn :
- Animals, Antirheumatic Agents (pharmacology), Antirheumatic Agents (therapeutic use), Chloroquine (pharmacology), Chloroquine (therapeutic use), Drosophila melanogaster, Drug Evaluation, Preclinical, Female, HEK293 Cells, HeLa Cells, Humans, Lysosomes (drug effects), Lysosomes (metabolism), Male, Mutation, Missense, Polycystic Kidney, Autosomal Dominant (drug therapy), Polycystic Kidney, Autosomal Dominant (genetics), Polycystic Kidney, Autosomal Dominant (metabolism), Protein Stability, TRPP Cation Channels (genetics), TRPP Cation Channels (metabolism).
- MESH :
- chemical , genetics : TRPP Cation Channels.
- chemical , metabolism : TRPP Cation Channels.
- chemical , pharmacology : Antirheumatic Agents, Chloroquine.
- chemical , therapeutic use : Antirheumatic Agents, Chloroquine.
- drug effects : Lysosomes.
- drug therapy : Polycystic Kidney, Autosomal Dominant.
- genetics : Polycystic Kidney, Autosomal Dominant.
- metabolism : Lysosomes, Polycystic Kidney, Autosomal Dominant.
- Animals, Drosophila melanogaster, Drug Evaluation, Preclinical, Female, HEK293 Cells, HeLa Cells, Humans, Male, Mutation, Missense, Protein Stability.
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.
DOI: 10.1016/j.kint.2015.11.015
PubMed: 26924047
Affiliations:
- Allemagne, États-Unis
- Bade-Wurtemberg, District de Fribourg-en-Brisgau, District de Karlsruhe, Maryland
- Fribourg-en-Brisgau, Heidelberg
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Le document en format XML
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médicament</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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. </div></front></TEI><affiliations><list><country><li>Allemagne</li><li>États-Unis</li></country><region><li>Bade-Wurtemberg</li><li>District de Fribourg-en-Brisgau</li><li>District de Karlsruhe</li><li>Maryland</li></region><settlement><li>Fribourg-en-Brisgau</li><li>Heidelberg</li></settlement></list><tree><country name="Allemagne"><region name="Bade-Wurtemberg"><name sortKey="Hofherr, Alexis" sort="Hofherr, Alexis" uniqKey="Hofherr A" first="Alexis" last="Hofherr">Alexis Hofherr</name></region><name sortKey="Kottgen, Michael" sort="Kottgen, Michael" uniqKey="Kottgen M" first="Michael" last="Köttgen">Michael Köttgen</name><name sortKey="Wagner, Claudius J" sort="Wagner, Claudius J" uniqKey="Wagner C" first="Claudius J" last="Wagner">Claudius J. Wagner</name></country><country name="États-Unis"><region name="Maryland"><name sortKey="Watnick, Terry" sort="Watnick, Terry" uniqKey="Watnick T" first="Terry" last="Watnick">Terry Watnick</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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