Role of Dopamine D2/D3 Receptors in Development, Plasticity, and Neuroprotection in Human iPSC-Derived Midbrain Dopaminergic Neurons

Bono, Federica; Savoia, Paola; Guglielmi, Adele; Gennarelli, Massimo; Piovani, Giovanna; Sigala, Sandra; Leo, Damiana; Espinoza, Stefano; Gainetdinov, Raul R.; Devoto, Paola; Spano, Pier Franco; Missale, Cristina; Fiorentini, Chiara

doi:10.1007/s12035-016-0376-3

Cited by 33 publications

(42 citation statements)

References 63 publications

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“…These results suggest that the structural plasticity of DA neurons is substantially promoted by the D3R, a conclusion supported by the finding that the neurotrophic effects of D2-like agonists were abolished by the specific D3R antagonist SB2770121A and were vanished in DA neurons derived from D3R-KO mice [ 21 , 31 ]. By using human-induced pluripotent stem cells (hiPSCs)-derived neurons form healthy subjects, we recently provided a widespread characterization of D3R expression and function, throughout the differentiation process, from hiPSCs toward the acquisition of a phenotype characteristic of authentic DA neurons [ 18 ]. In particular, we showed that the mRNA encoding for the D3R was already detected in the hiPSC stage and that the D3R is involved in the amplification of the multipotent/neuronal progenitor cell population before the acquisition of a finally differentiated DA phenotype.…”

Section: Structure and Function Of D3 Receptormentioning

confidence: 99%

“…These data are consistent with previously published data showing the prenatal expression of the D3R in rodents [ 37 , 38 , 39 ] and in human embryonic stem cells [ 40 ]. We have also shown that, in addition to its classical role as an autoreceptor [ 1 , 18 ], stimulation of D3R promotes neurotrophic effects [ 18 , 41 ] and plays a crucial role in triggering key intracellular events with neuroprotective potential [ 18 , 19 ].…”

Section: Structure and Function Of D3 Receptormentioning

confidence: 99%

“…Taken together, these data suggest that the D3R may be crucially involved in the control of DA neuron trophism during development [ 18 , 39 , 42 ], a property also shared with the D2R [ 43 , 44 ], and in counteracting early pathological events that may subsequently result in neurodegeneration [ 18 , 21 , 22 , 23 ].…”

Section: Structure and Function Of D3 Receptormentioning

confidence: 99%

“…Since nAChR and both D2R and D3R are extensively co-localized in both DA neuron cell bodies and nerve terminals, the possibility that functional interactions may occur between DA receptors and nAChR has been investigated and clearly demonstrated [ 87 ]. A cross-talk between D2R and nAChR in DA terminals has been reported, with nAChR-mediated stimulation of DA release being inhibited by the D2R [ 18 , 88 ]. This antagonistic cross-talk could be easily explained by the formation of a nAChR–D2R complex, since a physical interaction between β2* nAChR and D2R has been suggested by co-immunoprecipitation experiments [ 88 ].…”

Section: Interaction Of D3r and Nachr: Relevance For Neuroplasticimentioning

confidence: 99%

“…Moreover, there is substantial evidence that the D3R exerts neurotrophic, neuroprotective and neurorestorative effects on DA neurons. On this basis, a new and essential role for D3R-mediated neurotransmission has been suggested, both in preserving DA neuron homeostasis in physiological conditions and in counteracting neuronal alterations prodromal to neurodegeneration [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Dopamine D3 Receptor Heteromerization: Implications for Neuroplasticity and Neuroprotection

et al. 2020

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The dopamine (DA) D3 receptor (D3R) plays a pivotal role in the control of several functions, including motor activity, rewarding and motivating behavior and several aspects of cognitive functions. Recently, it has been reported that the D3R is also involved in the regulation of neuronal development, in promoting structural plasticity and in triggering key intracellular events with neuroprotective potential. A new role for D3R-dependent neurotransmission has thus been proposed both in preserving DA neuron homeostasis in physiological conditions and in preventing pathological alterations that may lead to neurodegeneration. Interestingly, there is evidence that nicotinic acetylcholine receptors (nAChR) located on DA neurons also provide neurotrophic support to DA neurons, an effect requiring functional D3R and suggesting the existence of a positive cross-talk between these receptor systems. Increasing evidence suggests that, as with the majority of G protein-coupled receptors (GPCR), the D3R directly interacts with other receptors to form new receptor heteromers with unique functional and pharmacological properties. Among them, we recently identified a receptor heteromer containing the nAChR and the D3R as the molecular effector of nicotine-mediated neurotrophic effects. This review summarizes the functional and pharmacological characteristics of D3R, including the capability to form active heteromers as pharmacological targets for specific neurodegenerative disorders. In particular, the molecular and functional features of the D3R-nAChR heteromer will be especially discussed since it may represent a possible key etiologic effector for DA-related pathologies, such as Parkinson’s disease (PD), and a target for drug design.

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Section: Structure and Function Of D3 Receptormentioning

confidence: 99%

Section: Structure and Function Of D3 Receptormentioning

confidence: 99%

Section: Structure and Function Of D3 Receptormentioning

confidence: 99%

Section: Interaction Of D3r and Nachr: Relevance For Neuroplasticimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dopamine D3 Receptor Heteromerization: Implications for Neuroplasticity and Neuroprotection

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Dopamine D1 + D3 receptor density may correlate with parkinson disease clinical features

Yang

Knight

et al. 2020

Ann Clin Transl Neurol

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ObjectiveDopamine D2‐like receptors – mainly dopamine D2 receptors (D2R) and dopamine D3 receptors (D3R) – are believed to be greatly involved in the pathology of Parkinson disease (PD) progression. However, these receptors have not been precisely examined in PD patients. Our aim was to quantitatively calculate the exact densities of dopamine D1 receptors (D1R), D2R, and D3R in control, Alzheimer disease (AD), and Lewy body disease (LBD) patients (including PD, Dementia with Lewy bodies, and Parkinson disease dementia); and analyze the relationship between dopamine receptors and clinical PD manifestations.MethodsWe analyzed the densities of D1R, D2R, and D3R in the striatum and substantia nigra (SN) using a novel quantitative autoradiography procedure previously developed by our group. We also examined the expression of D2R and D3R mRNA in the striatum by in situ hybridization.ResultsThe results showed that although no differences of striatal D1R were found among all groups; D2R was significantly decreased in the striatum of PD patients when compared with control and AD patients. Some clinical manifestations: age of onset, PD stage, dopamine responsiveness, and survival time after onset; showed a better correlation with striatal D1R + D3R densities combined compared to D1R or D3R alone.InterpretationThere is a possibility that we may infer the results in diagnosis, treatment, and prognosis of PD by detecting D1R + D3R as opposed to using dopamine D1 or D3 receptors alone. This is especially true for elderly patients with low D2R expression as is common in this disease.

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Extracellular clusterin limits the uptake of α‐synuclein fibrils by murine and human astrocytes

Filippini

Mutti

Faustini

et al. 2020

Glia

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The progressive neuropathological damage seen in Parkinson's disease (PD) is thought to be related to the spreading of aggregated forms of α‐synuclein. Clearance of extracellular α‐synuclein released by degenerating neurons may be therefore a key mechanism to control the concentration of α‐synuclein in the extracellular space. Several molecular chaperones control misfolded protein accumulation in the extracellular compartment. Among these, clusterin, a glycoprotein associated with Alzheimer's disease, binds α‐synuclein aggregated species and is present in Lewy bodies, intraneuronal aggregates mainly composed by fibrillary α‐synuclein. In this study, using murine primary astrocytes with clusterin genetic deletion, human‐induced pluripotent stem cell (iPSC)‐derived astrocytes with clusterin silencing and two animal models relevant for PD we explore how clusterin affects the clearance of α‐synuclein aggregates by astrocytes. Our findings showed that astrocytes take up α‐synuclein preformed fibrils (pffs) through dynamin‐dependent endocytosis and that clusterin levels are modulated in the culture media of cells upon α‐synuclein pffs exposure. Specifically, we found that clusterin interacts with α‐synuclein pffs in the extracellular compartment and the clusterin/α‐synuclein complex can be internalized by astrocytes. Mechanistically, using clusterin knock‐out primary astrocytes and clusterin knock‐down hiPSC‐derived astrocytes we observed that clusterin limits the uptake of α‐synuclein pffs by cells. Interestingly, we detected increased levels of clusterin in the adeno‐associated virus‐ and the α‐synuclein pffs‐ injected mouse model, suggesting a crucial role of this chaperone in the pathogenesis of PD. Overall, our observations indicate that clusterin can limit the uptake of extracellular α‐synuclein aggregates by astrocytes and, hence, contribute to the spreading of Parkinson pathology.

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Role of Dopamine D2/D3 Receptors in Development, Plasticity, and Neuroprotection in Human iPSC-Derived Midbrain Dopaminergic Neurons

Cited by 33 publications

References 63 publications

Dopamine D3 Receptor Heteromerization: Implications for Neuroplasticity and Neuroprotection

Dopamine D3 Receptor Heteromerization: Implications for Neuroplasticity and Neuroprotection

Dopamine D1 + D3 receptor density may correlate with parkinson disease clinical features

Extracellular clusterin limits the uptake of α‐synuclein fibrils by murine and human astrocytes

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