Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ contributes to dopamine cell loss in Parkinson's disease

Arcuri, Ludovico; Viaro, Riccardo; Bido, Simone; Longo, Francesco; Calcagno, Mariangela; Fernagut, Pierre‐Olivier; Zaveri, Nurulain T.; Calò, Girolamo; Bézard, Erwan; Morari, Michele

doi:10.1016/j.nbd.2016.01.016

Cited by 26 publications

(27 citation statements)

References 78 publications

(136 reference statements)

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“…We recently addressed this issue, adopting a combined genetic and pharmacological approach [6]. First, consistent with data in ppN/OFQ -/- mice, we found that acute MPTP (4 x 20 mg/Kg i.p., every 90 min) caused a lesser reduction of nigral DA cells in NOP receptor knock-out (NOP -/- ) mice (40%) with respect to NOP+/+ controls (75%).…”

supporting

confidence: 76%

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Parkinson’s disease: no NOP, new hope

Arcuri¹,

Mercatelli²,

Morari³

2016

Oncotarget

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supporting

confidence: 76%

“…Although more evidence needs to be collected to claim that endogenous N/OFQ contributes to DA cell loss also in human PD, NOP receptor antagonists hold promise as symptomatic and disease-modifying agents in PD therapy [5, 6]. …”

mentioning

confidence: 99%

Parkinson’s disease: no NOP, new hope

Arcuri¹,

Mercatelli²,

Morari³

2016

Oncotarget

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“…Using a carefully designed bioinformatical analysis pipeline, we investigated the evolution of gene expression profiles, leading up to early PD-like neurodegeneration, and uncovered the underlying molecular events, in this model. 3 3.70E-08…”

Section: Discussionmentioning

confidence: 99%

“…Altered GPCR-related pathways were linked to Nociceptin (NOP ), C-C chemokine-receptor 1 (CCR1 ), and Sphingosine-1 phosphate-receptor 1 (S1P1 ) signaling. NOP is an inhibitory neuropeptide which may promote SN less loss in PD: its genetic deletion protects SN neurons against MPTP in mice, and the inhibition of its receptor protects the same neurons in a rat model of α-syn toxicity [3]. CCR1 is typically microglial and its product participates the recruitment of immune cells, but it is also expressed in the ventral midbrain during development, where it is involved in neuronal differentiation of DA neurons [24].…”

Section: Age-dependent Pathway/go Changesmentioning

confidence: 99%

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Hendrickx

Garcia

Ashrafi

et al. 2020

Preprint

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Understanding Parkinson's disease (PD) in particular in its earliest phases is important for diagnosis and treatment. However, human brain samples are collected post-mortem, reflecting mainly end stage disease. Because brain samples of mouse models can be collected at any stage of the disease process, they are useful to investigate PD progression. Here, we compare ventral midbrain transcriptomics profiles from α-synuclein transgenic mice with a progressive, early PD-like striatum neurodegeneration across different ages using pathway, gene set and network analysis methods. Our study uncovers statistically significant altered genes across ages and between genotypes with known, suspected or unknown function in PD pathogenesis and key pathways associated with disease progression. Among those are genotype-dependent alterations associated with synaptic plasticity, neurotransmission, as well as mitochondria-related genes and dysregulation of lipid metabolism. Age-dependent changes were among others observed in neuronal and synaptic activity, calcium homeostasis, and membrane receptor signaling pathways, many of which linked to G-protein coupled receptors. Most importantly, most changes occurred before neurodegeneration was detected in this model, which points to a sequence of gene expression events that may be relevant for disease initiation and progression. It is tempting to speculate that molecular changes similar to those changes observed in our model happen in midbrain dopaminergic neurons before they start to degenerate. In other words, we believe we have uncovered molecular changes that accompany the progression from preclinical to early PD. 1/30 models provide a useful means to investigate PD-associated molecular changes, in particular those preceding nigro-striatal degeneration. The elucidation of such early changes can shed light into disease causation and drivers of disease progression, thus in turn pointing to novel targets for intervention as well as biomarkers [16,45].Whole transcriptome analysis enables to compare thousands of genes between two or more groups [9], and provides a valuable method for identifying coordinated changes in gene expression patterns that are not captured by single-gene or protein measurement approaches [59]. Despite of these advantages, only a limited amount of studies have used transcriptomics on α-synuclein-based transgenic mouse models for PD [13, 67, 71-73, 94, 98]. Alpha-synuclein, a pre-synaptic protein believed to be a moderator of the synaptic vesicle cycle, is a major component of Lewy bodies [87]. In addition, mutations or multiplications in its genes leads to familiar forms of PD [26,46]. Transcriptomics studies on α-synuclein-based transgenic mouse models for PD have only looked at differentially expressed genes (DEGs) in relation to pre-defined cellular pathways or gene sets from public annotation databases [13,67,[71][72][73]94]. Most of them used only one [71][72][73] or two age groups [13,67,94,98] of the mouse model for their analyses, and some of them were perform...

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“…A Leica DM6000B motorized microscope coupled with the Mercator Pro software (Mercator Digital Imaging System, Explora Nova, La Rochelle, France) was used [2, 5, 7]. Counting was performed on at least 5 consecutive 50 μm thick slices, magnified at 40X.…”

Section: Methodsmentioning

confidence: 99%

Age-dependent dopamine transporter dysfunction and Serine129 phospho-α-synuclein overload in G2019S LRRK2 mice

Longo

Mercatelli

Novello

et al. 2017

acta neuropathol commun

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson’s disease. Here, we investigated whether the G2019S LRRK2 mutation causes morphological and/or functional changes at nigro-striatal dopamine neurons. Density of striatal dopaminergic terminals, nigral cell counts, tyrosine hydroxylase protein levels as well as exocytotic dopamine release measured in striatal synaptosomes, or striatal extracellular dopamine levels monitored by in vivo microdialysis were similar between ≥12-month-old G2019S knock-in mice and wild-type controls. In vivo striatal dopamine release was insensitive to the LRRK2 inhibitor Nov-LRRK2-11, and was elevated by the membrane dopamine transporter blocker GBR-12783. However, G2019S knock-in mice showed a blunted neurochemical and motor activation response to GBR-12783 compared to wild-type controls. Western blot and dopamine uptake analysis revealed an increase in dopamine transporter levels and activity in the striatum of 12-month-old G2019S KI mice. This phenotype correlated with a reduction in vesicular monoamine transporter 2 levels and an enhancement of vesicular dopamine uptake, which was consistent with greater resistance to reserpine-induced hypolocomotion. These changes were not observed in 3-month-old mice. Finally, Western blot analysis revealed no genotype difference in striatal levels of endogenous α-synuclein or α-synuclein bound to DOPAL (a toxic metabolite of dopamine). However, Serine129-phosphorylated α-synuclein levels were higher in 12-month-old G2019S knock-in mice. Immunohistochemistry confirmed this finding, also showing no genotype difference in 3-month-old mice. We conclude that the G2019S mutation causes progressive dysfunctions of dopamine transporters, along with Serine129-phosphorylated α-synuclein overload, at striatal dopaminergic terminals, which are not associated with dopamine homeostasis dysregulation or neuron loss but might contribute to intrinsic dopaminergic terminal vulnerability. We propose G2019S knock-in mice as a presymptomatic Parkinson’s disease model, useful to investigate the pathogenic interaction among genetics, aging, and internal or environmental factors leading to the disease.

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Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ contributes to dopamine cell loss in Parkinson's disease

Cited by 26 publications

References 78 publications

Parkinson’s disease: no NOP, new hope

Parkinson’s disease: no NOP, new hope

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Age-dependent dopamine transporter dysfunction and Serine129 phospho-α-synuclein overload in G2019S LRRK2 mice

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