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Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons.

ABSTRACT: Sigma-1 receptor (?1R) has been reported to be decreased in nigrostriatal motor system of Parkinson's disease patients. Using heterozygous and homozygous ?1R knockout (?1R+/- and ?1R-/-) mice, we investigated the influence of ?1R deficiency on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-impaired nigrostriatal motor system. The injection of MPTP for 5 weeks in wild-type mice (MPTP-WT mice), but not in ?1R+/- or ?1R-/- mice (MPTP-?1R+/- or MPTP-?1R-/- mice), caused motor deficits and ~40% death of dopaminergic neurons in substantia nigra pars compacta with an elevation of N-methyl-d-aspartate receptor (NMDAr) NR2B phosphorylation. The ?1R antagonist NE100 or the NR2B inhibitor Ro25-6981 could alleviate the motor deficits and the death of dopaminergic neurons in MPTP-WT mice. By contrast, MPTP-?1R+/- mice treated with the ?1R agonist PRE084 or MPTP-?1R-/- mice treated with the NMDAr agonist NMDA appeared to have similar motor deficits and loss of dopaminergic neurons as MPTP-WT mice. The pharmacological or genetic inactivation of ?1R suppressed the expression of dopamine transporter (DAT) in substantia nigra, which was corrected by NMDA. The activation of ?1R by PRE084 enhanced the DAT expression in WT mice or ?1R+/- mice. By contrast, the level of vesicular monoamine transporter 2 (VMAT2) in ?1R+/- mice or ?1R-/- mice had no difference from WT mice. Interestingly, MPTP-WT mice showed the reduction in the levels of DAT and VMAT2, but MPTP-?1R-/- mice did not. The inactivation of ?1R by NE100 could prevent the reduction of VMAT2 in MPTP-WT mice. In addition, the activation of microglia cells in substantia nigra was equally enhanced in MPTP-WT mice and MPTP-?1R-/- mice. The number of activated astrocytes in MPTP-?1R-/- mice was less than that in MPTP-WT mice. The findings indicate that the ?1R deficiency through suppressing NMDAr function and DAT expression can reduce MPTP-induced death of dopaminergic neurons and parkinsonism.

SUBMITTER: Hong J

PROVIDER: S-EPMC4650739 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons.

Hong J J Sha S S Zhou L L Wang C C Yin J J Chen L L

Cell death & disease 20150723

Sigma-1 receptor (σ1R) has been reported to be decreased in nigrostriatal motor system of Parkinson's disease patients. Using heterozygous and homozygous σ1R knockout (σ1R+/- and σ1R-/-) mice, we investigated the influence of σ1R deficiency on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-impaired nigrostriatal motor system. The injection of MPTP for 5 weeks in wild-type mice (MPTP-WT mice), but not in σ1R+/- or σ1R-/- mice (MPTP-σ1R+/- or MPTP-σ1R-/- mice), caused motor deficits and ~40% ...[more]

PMID: 26203861

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Project description:BACKGROUND:Mutations in glucocerebrosidase (GBA) cause Gaucher disease (GD) and increase the risk of developing Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Since both genetic and environmental factors contribute to the pathogenesis of sporadic PD, we investigated the susceptibility of nigrostriatal dopamine (DA) neurons in L444P GBA heterozygous knock-in (GBA +/L444P ) mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective dopaminergic mitochondrial neurotoxin. METHOD:We used GBA +/L444P mice, ?-synuclein knockout (SNCA -/- ) mice at 8 months of age, and adeno-associated virus (AAV)-human GBA overexpression to investigate the rescue effect of DA neuronal loss and susceptibility by MPTP. Mitochondrial morphology and functional assay were used to identify mitochondrial defects in GBA +/L444P mice. Motor behavioral test, immunohistochemistry, and HPLC were performed to measure dopaminergic degeneration by MPTP and investigate the relationship between GBA mutation and ?-synuclein. Mitochondrial immunostaining, qPCR, and Western blot were also used to study the effects of ?-synuclein knockout or GBA overexpression on MPTP-induced mitochondrial defects and susceptibility. RESULTS:L444P GBA heterozygous mutation reduced GBA protein levels, enzymatic activity and a concomitant accumulation of ?-synuclein in the midbrain of GBA +/L444P mice. Furthermore, the deficiency resulted in defects in mitochondria of cortical neurons cultured from GBA +/L444P mice. Notably, treatment with MPTP resulted in a significant loss of dopaminergic neurons and striatal dopaminergic fibers in GBA +/L444P mice compared to wild type (WT) mice. Levels of striatal DA and its metabolites were more depleted in the striatum of GBA +/L444P mice. Behavioral deficits, neuroinflammation, and mitochondrial defects were more exacerbated in GBA +/L444P mice after MPTP treatment. Importantly, MPTP induced PD-like symptoms were significantly improved by knockout of ?-synuclein or augmentation of GBA via AAV5-hGBA injection in both WT and GBA +/L444P mice. Intriguingly, the degree of reduction in MPTP induced PD-like symptoms in GBA +/L444P ?-synuclein (SNCA) -/- mice was nearly equal to that in SNCA -/- mice after MPTP treatment. CONCLUSION:Our results suggest that GBA deficiency due to L444P GBA heterozygous mutation and the accompanying accumulation of ?-synuclein render DA neurons more susceptible to MPTP intoxication. Thus, GBA and ?-synuclein play dual physiological roles in the survival of DA neurons in response to the mitochondrial dopaminergic neurotoxin, MPTP.

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Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons.

Publications

Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons.

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