Orphan Receptor GPR88 as an Emerging Neurotherapeutic Target

Ye, Na; Li, Bang; Mao, Qi; Wold, Eric A.; Tian, Sheng; Allen, John A.; Zhou, Jia

doi:10.1021/acschemneuro.8b00572

Cited by 27 publications

(93 citation statements)

References 83 publications

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“…Lower expression of AK4, a mitochondrial phosphotransferase, has been observed in the late PD [29]. GPR88, a Gi/o coupled orphan receptor, has been proposed as a PD target, due to its association with D2 receptor signaling and its involvement in cognitive and motor functions [101]. Finally, RILPL2 is involved in ciliogenesis linked to downstream LRRK2 -dependent phosphorylation of Rabs [89].…”

Section: Age-dependent Degsmentioning

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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Section: Age-dependent Degsmentioning

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

View full text Add to dashboard Cite

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“…From their localisation in striatal output cells, GPR88 receptors are strategically sited to modulate the function of several cortico‐striato‐thalamic loops, suggesting possible relevance as a target for the treatment of neuropsychiatric disorders. Indeed the GPR88 gene has been genetically associated with psychosis, 16 although it is not currently clear whether its expression and/or activity is altered in idiopathic patients 17 . Currently available treatments for schizophrenia are centred on the blockade of postsynaptic populations of dopamine (mainly D2) receptors in mesolimbic structures, for the amelioration of positive symptoms.…”

Section: Introductionmentioning

confidence: 99%

Impaired working memory, cognitive flexibility and reward processing in mice genetically lacking Gpr88: Evidence for a key role for Gpr88 in multiple cortico‐striatal‐thalamic circuits

Thomson

Openshaw

Mitchell

et al. 2020

Genes Brain and Behavior

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The GPR88 orphan G protein‐coupled receptor is expressed throughout the striatum, being preferentially localised in medium spiny neurons. It is also present in lower densities in frontal cortex and thalamus. Rare mutations in humans suggest a role in cognition and motor function, while common variants are associated with psychosis. Here we evaluate the influence of genetic deletion of GPR88 upon performance in translational tasks interrogating motivation, reward evaluation and cognitive function. In an automated radial arm maze ‘N‐back’ working memory task, Gpr88 KO mice showed impaired correct responding, suggesting a role for GPR88 receptors in working memory circuitry. Associative learning performance was similar to wild‐type controls in a touchscreen task but performance was impaired at the reversal learning stage, suggesting cognitive inflexibility. Gpr88 KO mice showed higher breakpoints, reduced latencies and lengthened session time in a progressive ratio task consistent with enhanced motivation. Simultaneously, locomotor hyperactivity was apparent in this task, supporting previous findings of actions of GPR88 in a cortico‐striatal‐thalamic motor loop. Evidence for a role of GPR88 in reward processing was demonstrated in a touchscreen‐based equivalent of the Iowa gambling task. Although both Gpr88 KO and wild‐type mice showed a preference for an optimum contingency choice, Gpr88 KO mice selected more risky choices at the expense of more advantageous lower risk options. Together these novel data suggest that striatal GPR88 receptors influence activity in a range of procedures integrated by prefrontal, orbitofrontal and anterior cingulate cortico‐striatal‐thalamic loops leading to altered cognitive, motivational and reward evaluation processes.

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“…This gene encodes a brain-specific G protein-coupled receptor that plays a role in dopaminergic function. This cell surface receptor which is involved in the recognition of iRBCs (infected red blood cells) [44] is also emerging as a novel drug target for central nervous system disorders including schizophrenia, Parkinson's disease (PD), and anxiety [45]. Another new key player of CM was the glycoprotein nonmetastatic melanoma protein B (GPNMB), a glycoprotein observed upon tissue damage and inflammation and associated with astrocytes, microglia, and macrophages.…”

mentioning

confidence: 99%

Understanding Human Cerebral Malaria through a Blood Transcriptomic Signature: Evidences for Erythrocyte Alteration, Immune/Inflammatory Dysregulation, and Brain Dysfunction

Cabantous

Poudiougou

Bergon

et al. 2020

Mediators of Inflammation

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Background. Cerebral malaria (CM), a reversible encephalopathy affecting young children, is a medical emergency requiring rapid clinical assessment and treatment. However, understanding of the genes/proteins and the biological pathways involved in the disease outcome is still limited. Methods. We have performed a whole transcriptomic analysis of blood samples from Malian children with CM or uncomplicated malaria (UM). Hierarchical clustering and pathway, network, and upstream regulator analyses were performed to explore differentially expressed genes (DEGs). We validated gene expression for 8 genes using real-time quantitative PCR (RT-qPCR). Plasma levels were measured for IP-10/CXCL10 and IL-18. Results. A blood RNA signature including 538 DEGs (∣FC∣≥2.0, adjusted P value ≤ 0.01) allowed to discriminate between CM and UM. Ingenuity Pathway Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed novel genes and biological pathways related to immune/inflammatory responses, erythrocyte alteration, and neurodegenerative disorders. Gene expressions of CXCL10, IL12RB2, IL18BP, IL2RA, AXIN2, and NET were significantly lower in CM whereas ARG1 and SLC6A9 were higher in CM compared to UM. Plasma protein levels of IP-10/CXCL10 were significantly lower in CM than in UM while levels of IL-18 were higher. Interestingly, among children with CM, those who died from a complication of malaria tended to have higher concentrations of IP-10/CXCL10 and IFN-γ than those who recovered. Conclusions. This study identified some new factors and mechanisms that play crucial roles in CM and characterized their respective biological pathways as well as some upstream regulators.

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Orphan Receptor GPR88 as an Emerging Neurotherapeutic Target

Cited by 27 publications

References 83 publications

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

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

Impaired working memory, cognitive flexibility and reward processing in mice genetically lacking Gpr88: Evidence for a key role for Gpr88 in multiple cortico‐striatal‐thalamic circuits

Understanding Human Cerebral Malaria through a Blood Transcriptomic Signature: Evidences for Erythrocyte Alteration, Immune/Inflammatory Dysregulation, and Brain Dysfunction

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