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 beta-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.

Bonsi, P., Ponterio, G., Vanni, V., Tassone, A., Sciamanna, G., Migliarini, S., et al. (2019). RGS9-2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models. EMBO MOLECULAR MEDICINE, 11(1) [10.15252/emmm.201809283].

RGS9-2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models

Ponterio G.;Vanni V.;Tassone A.;Sciamanna G.;Martella G.;Mercuri N. B.;D'Amelio M.;Pisani A.
2019

Abstract

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 beta-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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/26 - Neurologia
eng
Con Impact Factor ISI
beta‐arrestin; lysosomal degradation; striatum; Animals; Corpus Striatum; Disease Models, Animal; Dystonia Musculorum Deformans; Gene Expression; Gene Knockdown Techniques; Mice, Inbred C57BL; Microfilament Proteins; Molecular Chaperones; Nerve Tissue Proteins; RGS Proteins; Receptors, Dopamine D2; Signal Transduction
Bonsi, P., Ponterio, G., Vanni, V., Tassone, A., Sciamanna, G., Migliarini, S., et al. (2019). RGS9-2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models. EMBO MOLECULAR MEDICINE, 11(1) [10.15252/emmm.201809283].
Bonsi, P; Ponterio, G; Vanni, V; Tassone, A; Sciamanna, G; Migliarini, S; Martella, G; Meringolo, M; Dehay, B; Doudnikoff, E; Zachariou, V; Goodchild, Re; Mercuri, Nb; D'Amelio, M; Pasqualetti, M; Bezard, E; Pisani, A
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/218165
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