GPR37 has recently been shown to be a substrate of parkin and it was renamed parkin associated endothelin-like receptor (Pael-R). Mutations of the parkin gene may cause autosomal-recessive juvenile Parkinson's disease (AR-JP). The Gpr37/Pael-R gene encodes an orphan G-protein coupled receptor that is highly expressed in mammalian brain, particularly in oligodendrocytes, Purkinje cells and neurons of CA3 hippocampal region and substantia nigra pars compacta (SNc). To investigate the receptor's function, we generated homozygous Gpr37 null mice. We verified the inactivation of the Gpr37 gene by Southern, Northern blot analyses and RT-PCR. Knock-out (KO) animals were viable and did not present any obvious abnormalities in gross brain morphology. We tested the mice in a model of Parkinson's disease (PD) by using the neurotoxic drug 1-methyl-4-phenyl-1, 2, 3, 6, -tetrahydropyridine (MPTP). When treated with MPTP (2x40 mg/kg, i. p, 6-h intervals) KO animals were more resistant to MPTP-induced degeneration of nigro-striatal dopaminergic cells. To further test the possible involvement of the GPR37 receptor in the pathophysiology of PD, we are measuring the number of tyrosine hydroxylase-immunoreactive SNc neurons and striatal dopaminergic terminals, as well as the levels of striatal dopamine in KO mice and WT littermates. Behavioural studies using the open field and rotarod tests are being performed to assess the locomotor activity and motor coordination of KO compared to WT mice. We hypothesise a role for the GPR37/Pael-R in the regulation of the nigro-striatal dopaminergic signalling pathways under specific stimuli. Further biochemical and behavioural analyses are in progress to better determine the role of GPR37 in the regulation of dopaminergic systems and its involvement in the molecular mechanisms underlying PD. Supported by: CNR-MURST L. 95/95-5%; CNR-MIUR "Genomica Funzionale" and MIUR-FIRB projects; European FP5 EUMORPHIA Network of Excellence.
GPR37/PAEL-R knock-out mice show abnormalities in nigro-striatal dopaminergic function
Mandillo S;Marazziti D;Golini E;Matteoni R;
2004
Abstract
GPR37 has recently been shown to be a substrate of parkin and it was renamed parkin associated endothelin-like receptor (Pael-R). Mutations of the parkin gene may cause autosomal-recessive juvenile Parkinson's disease (AR-JP). The Gpr37/Pael-R gene encodes an orphan G-protein coupled receptor that is highly expressed in mammalian brain, particularly in oligodendrocytes, Purkinje cells and neurons of CA3 hippocampal region and substantia nigra pars compacta (SNc). To investigate the receptor's function, we generated homozygous Gpr37 null mice. We verified the inactivation of the Gpr37 gene by Southern, Northern blot analyses and RT-PCR. Knock-out (KO) animals were viable and did not present any obvious abnormalities in gross brain morphology. We tested the mice in a model of Parkinson's disease (PD) by using the neurotoxic drug 1-methyl-4-phenyl-1, 2, 3, 6, -tetrahydropyridine (MPTP). When treated with MPTP (2x40 mg/kg, i. p, 6-h intervals) KO animals were more resistant to MPTP-induced degeneration of nigro-striatal dopaminergic cells. To further test the possible involvement of the GPR37 receptor in the pathophysiology of PD, we are measuring the number of tyrosine hydroxylase-immunoreactive SNc neurons and striatal dopaminergic terminals, as well as the levels of striatal dopamine in KO mice and WT littermates. Behavioural studies using the open field and rotarod tests are being performed to assess the locomotor activity and motor coordination of KO compared to WT mice. We hypothesise a role for the GPR37/Pael-R in the regulation of the nigro-striatal dopaminergic signalling pathways under specific stimuli. Further biochemical and behavioural analyses are in progress to better determine the role of GPR37 in the regulation of dopaminergic systems and its involvement in the molecular mechanisms underlying PD. Supported by: CNR-MURST L. 95/95-5%; CNR-MIUR "Genomica Funzionale" and MIUR-FIRB projects; European FP5 EUMORPHIA Network of Excellence.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
