RGS 9‐2 rescues dopamine D2 receptor levels and signaling in DYT 1 dystonia mouse models

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 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.

Maladaptive striatal plasticity and abnormal reward-learning in cervical dystonia

“…The average plasticity parameter values were a 1 = 0.83 ± 0.55, b 1 = 0.78 ± 0.27, a 2 = −0.97 ± 0.85, b 2 = −0.62 ± 0.37 for reward and a 1 = 0.93 ± 0.67, b 1 = 0.65 ± 0.31, a 2 = −0.93 ± 0.82, b 2 = −0.59 ± 0.38 for the loss avoidance task would be relevant to a broad range of focal dystonia phenotypes. More recently, increased lysosomal degradation has been identified as the molecular basis for decreased D2 receptor density in DYT1 dystonia, once again reinforcing the increasing central convergent role for D2R dysfunction in dystonia (Bonsi et al, 2019). The extent to which these results can be extended to focal forms, such as cervical dystonia, remains unclear; however, it is interesting to note that recently identified genes associated with a cranio-cervical phenotype, including GNAL, THAP1, and ANO3, share common roles in striatal signal transduction (Charlesworth et al, 2012;Kumar et al, 2014;Zakirova et al, 2018).…”

Effect of Gabapentin in a Neuropathic Pain Model in Mice Overexpressing Human Wild-Type or Human Mutated Torsin A

“…The hMT mice show slower learning and decreased motor activity during exposure to the open field at 9 months of age and also shorter stride length than non-transgenic mice, instead of an overt dystonic behavior [ 18 ]; the latter could be explained by the observed difference in the response to amphetamine, without alteration of pre-synaptic transporters or post-synaptic dopamine receptors and, thus, in the release or transport of dopamine [ 19 ]. An altered D2 dopaminergic signaling [ 20 , 21 , 22 , 23 , 24 ] that is suggestive of imbalance between dopaminergic and cholinergic neurotransmission in dystonia [ 25 ] and linked to disinhibition of striatal GABAergic synaptic activity [ 26 ] is displayed by DYT1 dystonia model mice. Incidentally, the D2 receptors dysfunction observed in hMT mice is counteracted by the pharmacological blockade of adenosine A2A receptors [ 27 ].…”

A2A Receptor Dysregulation in Dystonia DYT1 Knock-Out Mice

“…Male control and mutant mice were sacrificed at the age of 5–6 months. DNA was isolated and amplified from 1 to 2 mm tail fragments with the Extract-N-Amp Tissue polymerase chain reaction (PCR) kit (XNAT2 kit; Sigma-Aldrich Merck Life Science, Milan, Italy), and genotyping was performed as previously reported [ 17 ]. All the efforts were made to minimize the number of animals utilized and their suffering.…”

“…A common form of primary early onset generalized dystonia is caused by 3 bp deletion (GAG) in the coding region of the TOR1A (DYT1) gene, which results in a defective protein called torsinA, whose role in dystonia pathology is unclear [ 6 ]. In animal models for DYT1 dystonia, multiple lines of evidence revealed the impairment of dopamine receptor type 2 (D2 receptor), with D2 downregulation, sparse D2 synapses, reduced coupling between the D2 receptor and its cognate G proteins, as well as the loss of D2 dependent electrophysiological inhibition and severely altered synaptic plasticity in medium spiny neurons and cholinergic interneurons in the striatum [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Therefore, the striatum and D2 receptors have been considered central in the cellular pathomechanism underlying DYT1 dystonia [ 15 ].…”