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Article: Induced pluripotent stem cells for defining Parkinsonian patient subtypes: a further step toward precision medicine.

Bono, Federica / Missale, Cristina / Fiorentini, Chiara

2021 Volume 17, Issue 4, Page(s) 767–769

Language	English
Publishing date	2021-09-02
Publishing country	India
Document type	Journal Article
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.322448
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Article ; Online: Nerve growth factor, D2 receptor isoforms, and pituitary tumors.

Missale, Cristina

Endocrine

2012 Volume 42, Issue 3, Page(s) 466–467

MeSH term(s)	Animals ; Dopamine/pharmacology ; Dopamine/physiology ; Dopamine Agonists/pharmacology ; Humans ; Isomerism ; Nerve Growth Factor/physiology ; Pituitary Gland/cytology ; Pituitary Gland/metabolism ; Pituitary Gland, Anterior/drug effects ; Pituitary Gland, Anterior/metabolism ; Pituitary Neoplasms/physiopathology ; Prolactin/metabolism ; Receptors, Dopamine D2/physiology
Chemical Substances	Dopamine Agonists ; Receptors, Dopamine D2 ; Prolactin (9002-62-4) ; Nerve Growth Factor (9061-61-4) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2012-07-26
Publishing country	United States
Document type	Editorial
ZDB-ID	1194484-5
ISSN	1559-0100 ; 1355-008X ; 0969-711X
ISSN (online)	1559-0100
ISSN	1355-008X ; 0969-711X
DOI	10.1007/s12020-012-9756-2
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Article ; Online: Dopamine D3 Receptor Heteromerization: Implications for Neuroplasticity and Neuroprotection.

Bono, Federica / Mutti, Veronica / Fiorentini, Chiara / Missale, Cristina

Biomolecules

2020 Volume 10, Issue 7

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Humans ; Neuronal Plasticity ; Neuroprotection ; Protein Multimerization ; Receptors, Dopamine D3/chemistry ; Receptors, Dopamine D3/metabolism ; Receptors, Nicotinic/metabolism
Chemical Substances	Receptors, Dopamine D3 ; Receptors, Nicotinic
Language	English
Publishing date	2020-07-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom10071016
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Article ; Online: Differential effects of metformin on reductive activity and energy production in pituitary tumor cells compared to myogenic precursors.

Tulipano, Giovanni / Paghera, Simone / Missale, Cristina / Giustina, Andrea

Endocrine

2020 Volume 69, Issue 3, Page(s) 604–614

Abstract: Purpose: Given the multiple targets of metformin within cells, the mechanism by which it may exert a growth-inhibitory action on pituitary tumor cells in vitro remains to be explored. Previous research stressed metformin-induced changes in the activity ... ...

Abstract	Purpose: Given the multiple targets of metformin within cells, the mechanism by which it may exert a growth-inhibitory action on pituitary tumor cells in vitro remains to be explored. Previous research stressed metformin-induced changes in the activity of signaling pathways regulating cell growth and cell death. In this work, we investigated the effects of metformin on cell viability markers related to cell metabolic activity in rat pituitary tumor cells versus rat myogenic precursors as a model of normal proliferating somatic cells. Methods: We designed our experiments in order to use the MTT reduction as a marker of cellular reductive activity and the total cellular ATP levels as a marker of energy supply during short incubations with different metabolic substrates (sodium pyruvate, D-glucose, L-glutamine, sodium citrate). Then, we extended the analysis to extracellular glucose consumption, extracellular medium acidification and pyruvate dehydrogenase (PDH) complex activity. Results: Metformin was found to be effective in both cell types at the same concentrations, although the outcome of the treatment was quite the opposite. Unexpectedly, metformin increased the viability of subconfluent rat myoblasts. Rat pituitary tumor cells and myoblasts differed in the utilization of distinct metabolic substrates and the PDH complex activity. Metformin actions on reductive activity and ATP production were substrate-dependent. Conclusions: Overall, this work points out that metformin actions at the cellular level depend on metabolic features and metabolic requirements of cells. The pyruvate metabolic branch point is most likely to play a main role in the variability of cell response to metformin.
MeSH term(s)	Animals ; Cell Survival ; Glucose ; Metformin/pharmacology ; Pituitary Gland ; Pituitary Neoplasms/drug therapy ; Rats
Chemical Substances	Metformin (9100L32L2N) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2020-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1194484-5
ISSN	1559-0100 ; 1355-008X ; 0969-711X
ISSN (online)	1559-0100
ISSN	1355-008X ; 0969-711X
DOI	10.1007/s12020-020-02373-7
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Article: Recent Advances in Dopamine D3 Receptor Heterodimers: Focus on Dopamine D3 and D1 Receptor-Receptor Interaction and Striatal Function.

Bono, Federica / Mutti, Veronica / Tomasoni, Zaira / Sbrini, Giulia / Missale, Cristina / Fiorentini, Chiara

Current topics in behavioral neurosciences

2022

Abstract: G protein-coupled receptors (GPCR) heterodimers represent new entities with unique pharmacological, signalling, and trafficking properties, with specific distribution restricted to those cells where the two interacting receptors are co-expressed. Like ... ...

Abstract	G protein-coupled receptors (GPCR) heterodimers represent new entities with unique pharmacological, signalling, and trafficking properties, with specific distribution restricted to those cells where the two interacting receptors are co-expressed. Like other GPCR, dopamine D3 receptors (D3R) directly interact with various receptors to form heterodimers: data showing the D3R physical interaction with both GPCR and non-GPCR receptors have been provided including D3R interaction with other dopamine receptors. The aim of this chapter is to summarize current knowledge of the distinct roles of heterodimers involving D3R, focusing on the D3R interaction with the dopamine D1 receptor (D1R): the D1R-D3R heteromer, in fact, has been postulated in both ventral and motor striatum. Interestingly, since both D1R and D3R have been implicated in several pathological conditions, including schizophrenia, motor dysfunctions, and substance use disorders, the D1R-D3R heteromer may represent a potential drug target for the treatment of these diseases.
Language	English
Publishing date	2022-05-04
Publishing country	Germany
Document type	Journal Article
ISSN	1866-3370
ISSN	1866-3370
DOI	10.1007/7854_2022_353
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Article ; Online: G Protein-Dependent Activation of the PKA-Erk1/2 Pathway by the Striatal Dopamine D1/D3 Receptor Heteromer Involves Beta-Arrestin and the Tyrosine Phosphatase Shp-2.

Bono, Federica / Tomasoni, Zaira / Mutti, Veronica / Sbrini, Giulia / Kumar, Rajesh / Longhena, Francesca / Fiorentini, Chiara / Missale, Cristina

Biomolecules

2023 Volume 13, Issue 3

Abstract: The heteromer composed of dopamine D1 and D3 receptors (D1R-D3R) has been defined as a structure able to trigger Erk1/2 and Akt signaling in a G protein-independent, beta-arrestin 1-dependent way that is physiologically expressed in the ventral striatum ... ...

Abstract	The heteromer composed of dopamine D1 and D3 receptors (D1R-D3R) has been defined as a structure able to trigger Erk1/2 and Akt signaling in a G protein-independent, beta-arrestin 1-dependent way that is physiologically expressed in the ventral striatum and is likely involved in the control of locomotor activity. Indeed, abnormal levels of D1R-D3R heteromer in the dorsal striatum have been correlated with the development of L-DOPA-induced dyskinesia (LID) in Parkinson's disease patients, a motor complication associated with striatal D1R signaling, thus requiring Gs protein and PKA activity to activate Erk1/2. Therefore, to clarify the role of the D1R/D3R heteromer in LID, we investigated the signaling pathway induced by the heteromer using transfected cells and primary mouse striatal neurons. Collectively, we found that in both the cell models, D1R/D3R heteromer-induced activation of Erk1/2 exclusively required the D1R molecular effectors, such as Gs protein and PKA, with the contribution of the phosphatase Shp-2 and beta-arrestins, indicating that heterodimerization with the D3R abolishes the specific D3R-mediated signaling but strongly allows D1R signals. Therefore, while in physiological conditions the D1R/D3R heteromer could represent a mechanism that strengthens the D1R activity, its pathological expression may contribute to the abnormal PKA-Shp-2-Erk1/2 pathway connected with LID.
MeSH term(s)	Animals ; Mice ; beta-Arrestin 1 ; beta-Arrestins ; Dopamine ; GTP-Binding Proteins ; Levodopa/pharmacology ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 ; Protein Tyrosine Phosphatases ; Receptors, Dopamine D1 ; Receptors, Dopamine D3
Chemical Substances	beta-Arrestin 1 ; beta-Arrestins ; Dopamine (VTD58H1Z2X) ; GTP-Binding Proteins (EC 3.6.1.-) ; Levodopa (46627O600J) ; Mapk1 protein, mouse (EC 2.7.11.24) ; Mapk3 protein, mouse (EC 2.7.11.24) ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 (EC 3.1.3.48) ; Protein Tyrosine Phosphatases (EC 3.1.3.48) ; Receptors, Dopamine D1 ; Receptors, Dopamine D3 ; nuclear receptor subfamily 0, group B, member 2 ; Ptpn11 protein, mouse (EC 3.1.3.48)
Language	English
Publishing date	2023-03-03
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom13030473
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Article ; Online: Central nervous system interaction and crosstalk between nAChRs and other ionotropic and metabotropic neurotransmitter receptors.

Bono, Federica / Fiorentini, Chiara / Mutti, Veronica / Tomasoni, Zaira / Sbrini, Giulia / Trebesova, Hanna / Marchi, Mario / Grilli, Massimo / Missale, Cristina

Pharmacological research

2023 Volume 190, Page(s) 106711

Abstract: Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in both the peripheral and the central nervous systems. nAChRs exert a crucial modulatory influence on several brain biological processes; they are involved in a variety of ... ...

Abstract	Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in both the peripheral and the central nervous systems. nAChRs exert a crucial modulatory influence on several brain biological processes; they are involved in a variety of neuronal diseases including Parkinson's disease, Alzheimer's disease, epilepsy, and nicotine addiction. The influence of nAChRs on brain function depends on the activity of other neurotransmitter receptors that co-exist with nAChRs on neurons. In fact, the crosstalk between receptors is an important mechanism of neurotransmission modulation and plasticity. This may be due to converging intracellular pathways but also occurs at the membrane level, because of direct physical interactions between receptors. In this line, this review is dedicated to summarizing how nAChRs and other ionotropic and metabotropic receptors interact and the relevance of nAChRs cross-talks in modulating various neuronal processes ranging from the classical modulation of neurotransmitter release to neuron plasticity and neuroprotection.
MeSH term(s)	Receptors, Nicotinic/metabolism ; Central Nervous System/metabolism ; Neurons/metabolism ; Synaptic Transmission/physiology ; Brain/metabolism
Chemical Substances	Receptors, Nicotinic
Language	English
Publishing date	2023-02-26
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2023.106711
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Article ; Online: In-vitro Approaches to Investigate the Detrimental Effect of Light on Dopaminergic Neurons.

Fasciani, Irene / Petragnano, Francesco / Bono, Federica / Aloisi, Gabriella / Mutti, Veronica / Pardini, Carla / Carli, Marco / Scarselli, Marco / Vaglini, Francesca / Angelucci, Adriano / Fiorentini, Chiara / Lozzi, Luca / Missale, Cristina / Maggio, Roberto / Rossi, Mario

Neuroscience

2024 Volume 544, Page(s) 104–116

Abstract: Our recent study revealed that fluorescent lamp light can penetrate deep into the brain of mice and rats leading to the development of typical histological characteristics associated with Parkinson's disease such as the loss of dopamine neurons in the ... ...

Abstract	Our recent study revealed that fluorescent lamp light can penetrate deep into the brain of mice and rats leading to the development of typical histological characteristics associated with Parkinson's disease such as the loss of dopamine neurons in the substantia nigra. Monochromatic LED lights were thus used in this work to deepen our knowledge on the effects of the major wavelength peaks of fluorescent light on mouse and human dopaminergic cells. In particular, we exposed immortalized dopaminergic MN9D neuronal cells, primary cultures of mouse mesencephalic dopaminergic cells and human dopaminergic neurons differentiated from induced pluripotent stem cells (hiPSC) to different LED light wavelengths. We found that chronic exposure to LED light reduced overall undifferentiated MN9D cell number, with the most significant effects observed at wavelengths of 485 nm and 610 nm. Moreover, LED light especially at 610 nm was able to negatively impact on the survival of mouse mesencephalic dopaminergic cells and of human dopaminergic neurons derived from hiPSC. Notably, differentiated MN9D dopaminergic cells, which closely resemble mature dopamine neuronal phenotype, acutely exposed for 3 h at 610 nm, showed a clear increase in ROS production and cytotoxicity compared to controls undifferentiated MN9D cells. These increases were even more pronounced by the co-treatment with the oxidative agent H
MeSH term(s)	Humans ; Animals ; Rats ; Dopaminergic Neurons ; Parkinson Disease/pathology ; Hydrogen Peroxide/pharmacology ; Mesencephalon ; Substantia Nigra
Chemical Substances	Hydrogen Peroxide (BBX060AN9V)
Language	English
Publishing date	2024-01-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/j.neuroscience.2024.01.009
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Article ; Online: Structural Plasticity of Dopaminergic Neurons Requires the Activation of the D3R-nAChR Heteromer and the PI3K-ERK1/2/Akt-Induced Expression of c-Fos and p70S6K Signaling Pathway.

Mutti, Veronica / Bono, Federica / Tomasoni, Zaira / Bontempi, Leonardo / Guglielmi, Adele / Bolognin, Silvia / Schwamborn, Jens C / Missale, Cristina / Fiorentini, Chiara

Molecular neurobiology

2022 Volume 59, Issue 4, Page(s) 2129–2149

Abstract: We have previously shown that the heteromer composed by the dopamine D3 receptor (D3R) and the nicotinic acetylcholine receptor (nAChR) (D3R-nAChR heteromer) is expressed in dopaminergic neurons, activated by nicotine and represents the molecular unit ... ...

Abstract	We have previously shown that the heteromer composed by the dopamine D3 receptor (D3R) and the nicotinic acetylcholine receptor (nAChR) (D3R-nAChR heteromer) is expressed in dopaminergic neurons, activated by nicotine and represents the molecular unit that, in these neurons, contributes to the modulation of critical events such as structural plasticity and neuroprotection. We now extended this study by investigating the D3R-nAChR heteromer properties using various cell models such as transfected HEK293 cells, primary cultures of mouse dopaminergic neurons and human dopaminergic neurons derived from induced pluripotent stem cells.We found that the D3R-nAChR heteromer is the molecular effector that transduces the remodeling properties not only associated with nicotine but also with D3R agonist stimulation: neither nAChR nor D3R, in fact, when express as monomers, are able to elicit these effects. Moreover, strong and sustained activation of the PI3K-ERK1/2/Akt pathways is coupled with D3R-nAChR heteromer stimulation, leading to the expression of the immediate-early gene c-Fos and to sustained phosphorylation of cytosolic p70 ribosomal S6 kinase (p70S6K), critical for dendritic remodeling. By contrast, while D3R stimulation results in rapid and transient activation of both Erk1/2 and Akt, that is PI3K-dependent, stimulation of nAChR is associated with persistent activation of Erk1/2 and Akt, in a PI3K-independent way. Thus, the D3R-nAChR heteromer and its ability to trigger the PI3K-ERK1/2/Akt signaling pathways may represent a novel target for preserving dopaminergic neurons healthy and for conferring neuronal protection against injuries.
MeSH term(s)	Animals ; Dopaminergic Neurons/metabolism ; HEK293 Cells ; Humans ; MAP Kinase Signaling System ; Mice ; Nicotine/pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; Receptors, Dopamine D3/metabolism ; Receptors, Nicotinic/metabolism ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Signal Transduction
Chemical Substances	Proto-Oncogene Proteins c-fos ; Receptors, Dopamine D3 ; Receptors, Nicotinic ; Nicotine (6M3C89ZY6R) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Ribosomal Protein S6 Kinases, 70-kDa (EC 2.7.11.1)
Language	English
Publishing date	2022-01-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-022-02748-z
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Article ; Online: Dopamine Transporter/α-Synuclein Complexes Are Altered in the Post Mortem Caudate Putamen of Parkinson's Disease: An In Situ Proximity Ligation Assay Study.

Longhena, Francesca / Faustini, Gaia / Missale, Cristina / Pizzi, Marina / Bellucci, Arianna

International journal of molecular sciences

2018 Volume 19, Issue 6

Abstract: Parkinson's disease (PD) is characterized by the degeneration of the dopaminergic nigrostriatal neurons and the presence of Lewy bodies (LB) and Lewy neurites (LN) mainly composed of α-synuclein. By using the in situ proximity ligation assay (PLA), which ...

Abstract	Parkinson's disease (PD) is characterized by the degeneration of the dopaminergic nigrostriatal neurons and the presence of Lewy bodies (LB) and Lewy neurites (LN) mainly composed of α-synuclein. By using the in situ proximity ligation assay (PLA), which allows for the visualization of protein-protein interactions in tissues to detect dopamine transporter (DAT)/α-synuclein complexes, we previously described that these are markedly redistributed in the striatum of human α-synuclein transgenic mice at the phenotypic stage, showing dopamine (DA) release impairment without a DAT drop and motor symptoms. Here, we used the in situ PLA to investigate DAT/α-synuclein complexes in the caudate putamen of PD patients and age-matched controls. They were found to be redistributed and showed an increased size in PD patients, where we observed several neuropil-like and neuritic-like PLA-positive structures. In the PD brains, DAT immunolabeling showed a pattern similar to that of in situ PLA in areas with abundant α-synuclein neuropathology. This notwithstanding, the in situ PLA signal was only partially retracing DAT or α-synuclein immunolabeling, suggesting that a large amount of complexes may have been lost along with the degeneration process. These findings reveal a DAT/α-synuclein neuropathological signature in PD and hint that synaptic alterations involving striatal DAT may derive from α-synuclein aggregation.
MeSH term(s)	Aged ; Aged, 80 and over ; Animals ; Dopamine Plasma Membrane Transport Proteins/metabolism ; Female ; Humans ; Immunohistochemistry ; In Vitro Techniques ; Male ; Mice, Transgenic ; Parkinson Disease/metabolism ; alpha-Synuclein/metabolism
Chemical Substances	Dopamine Plasma Membrane Transport Proteins ; alpha-Synuclein
Language	English
Publishing date	2018-05-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms19061611
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