TY - JOUR
T1 - RGS9-2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models
AU - Bonsi, Paola
AU - Ponterio, Giulia
AU - Vanni, Valentina
AU - Tassone, Annalisa
AU - Sciamanna, Giuseppe
AU - Migliarini, Sara
AU - Martella, Giuseppina
AU - Meringolo, Maria
AU - Dehay, Benjamin
AU - Doudnikoff, Evelyne
AU - Zachariou, Venetia
AU - Goodchild, Rose E.
AU - Mercuri, Nicola B.
AU - D'Amelio, Marcello
AU - Pasqualetti, Massimo
AU - Bezard, Erwan
AU - Pisani, Antonio
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early-onset DYT1 dystonia. Nevertheless, the mechanisms that regulate D2 receptor signaling in health and disease remain poorly understood. Here, we identify a reduced D2 receptor binding, paralleled by an abrupt reduction in receptor protein level, in the striatum of juvenile Dyt1 mice. This occurs through increased lysosomal degradation, controlled by competition between β-arrestin 2 and D2 receptor binding proteins. Accordingly, we found lower levels of striatal RGS9-2 and spinophilin. Further, we show that genetic depletion of RGS9-2 mimics the D2 receptor loss of DYT1 dystonia striatum, whereas RGS9-2 overexpression rescues both receptor levels and electrophysiological responses in Dyt1 striatal neurons. This work uncovers the molecular mechanism underlying D2 receptor downregulation in Dyt1 mice and in turn explains why dopaminergic drugs lack efficacy in DYT1 patients despite significant evidence for striatal D2 receptor dysfunction. Our data also open up novel avenues for disease-modifying therapeutics to this incurable neurological disorder.
AB - Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early-onset DYT1 dystonia. Nevertheless, the mechanisms that regulate D2 receptor signaling in health and disease remain poorly understood. Here, we identify a reduced D2 receptor binding, paralleled by an abrupt reduction in receptor protein level, in the striatum of juvenile Dyt1 mice. This occurs through increased lysosomal degradation, controlled by competition between β-arrestin 2 and D2 receptor binding proteins. Accordingly, we found lower levels of striatal RGS9-2 and spinophilin. Further, we show that genetic depletion of RGS9-2 mimics the D2 receptor loss of DYT1 dystonia striatum, whereas RGS9-2 overexpression rescues both receptor levels and electrophysiological responses in Dyt1 striatal neurons. This work uncovers the molecular mechanism underlying D2 receptor downregulation in Dyt1 mice and in turn explains why dopaminergic drugs lack efficacy in DYT1 patients despite significant evidence for striatal D2 receptor dysfunction. Our data also open up novel avenues for disease-modifying therapeutics to this incurable neurological disorder.
KW - beta-arrestin
KW - lysosomal degradation
KW - striatum
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U2 - 10.15252/emmm.201809283
DO - 10.15252/emmm.201809283
M3 - Article
AN - SCOPUS:85058422371
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
M1 - e9283
ER -