Altered dopamine signaling and MPTP resistance in mice lacking the Parkinson's disease-associated GPR37/parkin-associated endothelin-like receptor

Marazziti, D.; Golini, Elisabetta; Mandillo, Silvia; Magrelli, Armando; Witke, Walter; Matteoni, Rafaele; Tocchini‐Valentini, Glauco P.

doi:10.1073/pnas.0403661101

Cited by 80 publications

(106 citation statements)

References 33 publications

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“…Parkin reduces GPR37 over-expression-induced cell death by ubiquitination in the presence of ubiquitin-conjugating enzymes (resident in the ER) thereby promoting receptor degradation [28]. GPR37 also regulates SN-striatum dopaminergic signalling [39] and has a protective eVect on SN neurones treated with the neurotoxin l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine [39]. As for TCP1, a member of the chaperonin family, limited information for its role in PD is available.…”

Section: Discussionmentioning

confidence: 99%

“…Two genes in the parkin pathway were up-regulated, GPR37 and TCP1. GPR37, an orphan G protein-coupled receptor, is a known substrate for parkin [28] and insoluble aggregates of this protein are found in juvenile PD patients [39]. Over-expressed GPR37 protein in dopaminergic neurones becomes unfolded and insoluble, accumulates in the endoplasmic reticulum (ER), inducing ER stress and neurodegeneration [28,29].…”

Section: Discussionmentioning

confidence: 99%

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Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

et al. 2007

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The identification of mutations that cause familial Parkinson's disease (PD) provides a framework for studies into pathways that may be perturbed also in the far more common, non-familial form of the disorder. Following this hypothesis, we have examined the gene regulatory network that links alpha-synuclein and parkin pathways with dopamine metabolism in neuropathologically verified cases of sporadic PD. By means of an in silico approach using a database of eukaryotic molecular interactions and a whole genome transcriptome dataset validated by qRT-PCR and histological methods, we found parkin and functionally associated genes to be upregulated in the lateral substantia nigra (SN). In contrast, alpha-synuclein and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene expression levels were significantly reduced in both the lateral and medial SN in PD. Gene expression for Septin 4, a member of the GTP-binding protein family involved in alpha-synuclein metabolism was elevated in the lateral parkinsonian SN. Additionally, catalase and mitogen-activated protein kinase 8 and poly (ADP-ribose) polymerase family member 1 (PARP1) known to function in DNA repair and cell death induction, all members of the dopamine synthesis pathway, were up-regulated in the lateral SN. In contrast, two additional PD-linked genes, glucocerebrosidase and nuclear receptor subfamily 4, group A, member 2 (NR4A2) showed reduced expression. We show that in sporadic PD, parkin, alpha-synuclein and dopamine pathways are co-deregulated. Alpha-synuclein is a member of all three gene regulatory networks. Our analysis results support the view that alpha-synuclein has a central role in the familial as well as the non-familial form of the disease and provide steps towards a pathway definition of PD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

et al. 2007

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“…After washing, sections were incubated with goat HRP polymer kit (Biocare Medical; GHP516) for 30 min at room temperature, followed by 3,3-diaminobenzidine tetrahydrochloride as the chromogen (45,46). The number of TH-positive neurons of the substantia nigra in each mouse was counted under light microscopy as described previously (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Liver X receptor β protects dopaminergic neurons in a mouse model of Parkinson disease

Dai

Tan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Parkinson disease (PD) is a progressive neurodegenerative disease whose progression may be slowed, but at present there is no pharmacological intervention that would stop or reverse the disease. Liver X receptor β (LXRβ) is a member of the nuclear receptor super gene family expressed in the central nervous system, where it is important for cortical layering during development and survival of dopaminergic neurons throughout life. In the present study we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of LXRβ as a target for prevention or treatment of PD. The dopaminergic neurons of the substantia nigra of LXRβ −/− mice were much more severely affected by MPTP than were those of their WT littermates. In addition, the number of activated microglia and GFAPpositive astrocytes was higher in the substantia nigra of LXRβ −/− mice than in WT littermates. Administration of the LXR agonist GW3965 to MPTP-treated WT mice protected against loss of dopaminergic neurons and of dopaminergic fibers projecting to the striatum, and resulted in fewer activated microglia and astroglia. Surprisingly, LXRβ was not expressed in the neurons of the substantia nigra but in the microglia and astroglia. We conclude that LXR agonists may have beneficial effects in treatment of PD by modulating the cytotoxic functions of microglia.midbrain | neurodegeneration | neuroinflammation P arkinson disease (PD) is a common neurodegenerative disorder whose clinical features include tremor, slowness of movement, stiffness, and postural instability (1). PD is characterized by microgliosis, astrogliosis, progressive degeneration of dopaminergic neurons, presence of Lewy bodies in dopaminergic neurons, and α-synuclein accumulation in substantia nigra pars compacta (2). Although there are drugs that alleviate symptoms of PD, chronic use of these drugs results in debilitating side effects (3), and none seems to halt the progression of the disease. The etiology of PD remains unknown, but environmental toxins, genetic factors, and mitochondrial dysfunction are thought to be involved. Neuroinflammation (microglial activation, astrogliosis, and lymphocyte infiltration) results in production of cytotoxic molecules (4-9) that are directly involved in neuronal degeneration. It is now recognized that targeting neuroinflammation is one intervention that can slow down the progression of PD (10).1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that targets rather specifically dopaminergic neurons that are involved in PD; its administration leads to severe and irreversible PD-like syndrome in humans and nonhuman primates, with most of the biochemical and pathological hallmarks of PD (11), i.e., marked loss of dopaminergic neurons, astrogliosis, and activated microglia in the substantia nigra pars compacta (12). In 2002, Wu et al. (13) showed that dopaminergic neurons in the substantia nigra could be protected from MPTP-induced damage by the tetracycline derivative minocycline. This capaci...

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“…Once the trained animals were able to stay on the rotating rod at 4 rpm for 60 s, they proceeded to the test. Mice were placed individually for four consecutive trials (30-min intertrial intervals) on the rod rotating at an accelerating speed from 4 to 40 (8, 16, 24, 32, 40) rpm in 300 s. The latency to fall off the rod and the maximal speed reached were automatically recorded (Marazziti et al, 2004).…”

Section: Rotarod Testmentioning

confidence: 99%

Perseverative responding and neuroanatomical alterations in adult heterozygous reeler mice are mitigated by neonatal estrogen administration

Macrı̀

Biamonte

Romano

et al. 2010

Psychoneuroendocrinology

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Summary According to the ''extreme-male brain'' theory, elevated fetal testosterone levels may partly explain the skewed sex ratio found in Autism Spectrum Disorders (ASD). Correcting this testosterone imbalance by increasing estrogen levels may mitigate the abnormal phenotype. Accordingly, while control heterozygous reeler (rl/+) male mice -a putative model of neuroanatomical and behavioral endophenotypes in ASD -show a decreased number of Purkinje cells (PC) compared to control wild-type (+/+) littermates, neonatal estradiol administration has been shown to correct this deficit in the short-term (i.e. on postnatal day 15). Here, we further investigated the neuroanatomical and behavioral abnormalities of rl/+ male mice and the potential compensatory effects of neonatal treatment with estradiol. In a longitudinal study, we observed that: i) infant rl/+ mice showed reduced motivation for social stimuli; ii) adult rl/+ male mice showed reduced cognitive flexibility; iii) the number of amygdalar parvalbuminpositive GABAergic interneurons were remarkably reduced in rl/+ mice; iv) neonatal estradiol administration into the cisterna magna reverted the abnormal profile both at the behavioral and at the neuroanatomical level in the amygdala but did not compensate for the cerebellar abnormalities in adulthood. This study supports the view that an increased excitation-toinhibition ratio in the cerebellum and in the amygdala during a critical window of development could be crucial to the social and cognitive phenotype of male rl/+ mice, and that acute estradiol treatment during this critical window may mitigate symptoms' severity. #

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Altered dopamine signaling and MPTP resistance in mice lacking the Parkinson's disease-associated GPR37/parkin-associated endothelin-like receptor

Cited by 80 publications

References 33 publications

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

Liver X receptor β protects dopaminergic neurons in a mouse model of Parkinson disease

Perseverative responding and neuroanatomical alterations in adult heterozygous reeler mice are mitigated by neonatal estrogen administration

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