The stimulation of adenosine A2A receptors ameliorates the pathological phenotype of fibroblasts from Niemann-Pick type C patients.
Niemann-Pick type C1 (NPC1) disease is a rare neurovisceral disorder characterized by intracellular accumulation of unesterified cholesterol, sphingolipids, and other lipids in the lysosomal compartment. A deregulation of lysosomal calcium has been identified as one of the earliest steps of the degenerative process. Since adenosine A2A receptors (A2ARs) control lysosome trafficking and pH, which closely regulates lysosomal calcium, we hypothesized a role for these receptors in NPC1. The aim of this study was to evaluate the effects of the A2AR agonist CGS21680 on human control and NPC1 fibroblasts. We show that CGS21680 raises lysosomal calcium levels and rescues mitochondrial functionality (mitochondrial inner membrane potential and expression of the complex IV of the mitochondrial respiratory chain), which is compromised in NPC1 cells. These effects are prevented by the selective blockade of A2ARs by the antagonist ZM241385. The effects of A2AR activation on lysosomal calcium are not mediated by the cAMP/PKA pathway but they appear to involve the phosphorylation of ERK1/2. Finally, CGS21680 reduces cholesterol accumulation (Filipin III staining), which is the main criterion currently used for identification of a compound or pathway that would be beneficial for NPC disease, and such an effect is prevented by the Ca(2+) chelator BAPTA-AM. Our findings strongly support the hypothesis that A2AR agonists may represent a therapeutic option for NPC1 and provide insights on their mechanisms of action.
Department of Cell Biology and Neuroscience, and Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy.
Sergio
S
Visentin
Chiara
C
De Nuccio
Antonietta
A
Bernardo
Rita
R
Pepponi
Antonella
A
Ferrante
Luisa
L
Minghetti
Patrizia
P
Popoli
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology*; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism* / Q000473:pathology; D010627:Phenethylamines / Q000494:pharmacology*; D010641:Phenotype; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D002784:Cholesterol; D000242:Cyclic AMP; D003576:Electron Transport Complex IV; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000241:Adenosine; D002118:Calcium