scholarly journals Involvement of the Protein Ras Homolog Enriched in the Striatum, Rhes, in Dopaminergic Neurons Degeneration: Link to Parkison’s Disease

2021 ◽  
Author(s):  
Marcello Serra ◽  
Annalisa Pinna ◽  
Giulia Costa ◽  
Alessandro Usiello ◽  
Massimo Pasqualetti ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Dorsal Striatum ◽  
Substantia Nigra Pars Compacta ◽  
Nigrostriatal System ◽  
Mrna Levels ◽  
Dopaminergic Transmission ◽  
A2a Receptors ◽  
Midbrain Dopaminergic Neurons ◽  
Pka Pathway ◽  
Adenosine A2a

Rhes is one of the most interesting proteins regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. It is expressed at high levels in the dorsal striatum, with a medial-to-lateral expression gradient reflecting that of both dopamine D2 and adenosine A2A receptors. Rhes is also present in the hippocampus, cerebral cortex, olfactory tubercle and bulb, substantia nigra pars compacta (SNc) and ventral tegmental area of the rodent brain. In line with Rhes-dependent regulation of dopaminergic transmission, several data showed that lack of Rhes enhanced cocaine and amphetamine-induced motor stimulation in mice. Previous studies showed that pharmacological depletion of dopamine significantly reduces Rhes mRNA levels in rodents, non-human primates and Parkinson’s disease (PD) patients, suggesting a link between dopaminergic innervation and physiological Rhes mRNA expression. Rhes protein binds to and activates striatal mTORC1, and modulates L-DOPA-induced dyskinesia in PD rodent models. Finally, Rhes is involved in the survival of mouse midbrain dopaminergic neurons of SNc, thus pointing towards a Rhes-dependent modulation of autophagy and mitophagy processes, and encouraging further investigations about mechanisms underlying dysfunctions of the nigrostriatal system.

scholarly journals Involvement of the Protein Ras Homolog Enriched in the Striatum, Rhes, in Dopaminergic Neurons’ Degeneration: Link to Parkinson’s Disease

2021 ◽  
Vol 22 (10) ◽  
pp. 5326
Author(s):  
Marcello Serra ◽  
Annalisa Pinna ◽  
Giulia Costa ◽  
Alessandro Usiello ◽  
Massimo Pasqualetti ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Dorsal Striatum ◽  
Substantia Nigra Pars Compacta ◽  
Nigrostriatal System ◽  
Mrna Levels ◽  
Dopaminergic Transmission ◽  
A2a Receptors ◽  
Midbrain Dopaminergic Neurons

Rhes is one of the most interesting genes regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. Rhes mRNA is expressed at high levels in the dorsal striatum, with a medial-to-lateral expression gradient reflecting that of both dopamine D2 and adenosine A2A receptors. Rhes transcript is also present in the hippocampus, cerebral cortex, olfactory tubercle and bulb, substantia nigra pars compacta (SNc) and ventral tegmental area of the rodent brain. In line with Rhes-dependent regulation of dopaminergic transmission, data showed that lack of Rhes enhanced cocaine- and amphetamine-induced motor stimulation in mice. Previous studies showed that pharmacological depletion of dopamine significantly reduces Rhes mRNA levels in rodents, non-human primates and Parkinson’s disease (PD) patients, suggesting a link between dopaminergic innervation and physiological Rhes mRNA expression. Rhes protein binds to and activates striatal mTORC1, and modulates L-DOPA-induced dyskinesia in PD rodent models. Finally, Rhes is involved in the survival of mouse midbrain dopaminergic neurons of SNc, thus pointing towards a Rhes-dependent modulation of autophagy and mitophagy processes, and encouraging further investigations about mechanisms underlying dysfunctions of the nigrostriatal system.

Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories

2021 ◽  
Vol 118 (40) ◽  
pp. e2111069118
Author(s):  
Theodoros Tsetsenis ◽  
Julia K. Badyna ◽  
Julianne A. Wilson ◽  
Xiaowen Zhang ◽  
Elizabeth N. Krizman ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Dorsal Hippocampus ◽  
Memory Formation ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Aversive Learning ◽  
Contextual Fear ◽  
Dopaminergic Transmission ◽  
Midbrain Dopaminergic Neurons ◽  
Midbrain Dopamine

Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here, we utilize anterograde and retrograde viral tracing methods to label midbrain dopaminergic projections to the dorsal hippocampus. We identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that sends direct projections to the dorsal hippocampus. Using optogenetic manipulations and mutant mice to control dopamine transmission in the hippocampus, we show that midbrain dopamine potently modulates aversive memory formation during encoding of contextual fear. Moreover, we demonstrate that dopaminergic transmission in the dorsal CA1 is required for the acquisition of contextual fear memories, and that this acquisition is sustained in the absence of catecholamine release from noradrenergic terminals. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus and show that the midbrain dopamine neuromodulation in the dorsal hippocampus is sufficient to maintain aversive memory formation.

scholarly journals From Inflammation to the Onset of Fibrosis through A2A Receptors in Kidneys from Deceased Donors

2020 ◽  
Vol 21 (22) ◽  
pp. 8826
Author(s):  
Elena Guillén-Gómez ◽  
Irene Silva ◽  
Núria Serra ◽  
Francisco Caballero ◽  
Jesús Leal ◽  
...  
Keyword(s):  
Deceased Donor ◽  
Inflammatory Factors ◽  
Mrna Levels ◽  
A2a Adenosine Receptor ◽  
A2a Receptors ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Pka Pathway ◽  
Tgf Β1 ◽  
M2 Phenotype

Pretransplant graft inflammation could be involved in the worse prognosis of deceased donor (DD) kidney transplants. A2A adenosine receptor (A2AR) can stimulate anti-inflammatory M2 macrophages, leading to fibrosis if injury and inflammation persist. Pre-implantation biopsies of kidney donors (47 DD and 21 living donors (LD)) were used to analyze expression levels and activated intracellular pathways related to inflammatory and pro-fibrotic processes. A2AR expression and PKA pathway were enhanced in DD kidneys. A2AR gene expression correlated with TGF-β1 and other profibrotic markers, as well as CD163, C/EBPβ, and Col1A1, which are highly expressed in DD kidneys. TNF-α mRNA levels correlated with profibrotic and anti-inflammatory factors such as TGF-β1 and A2AR. Experiments with THP-1 cells point to the involvement of the TNF-α/NF-κB pathway in the up-regulation of A2AR, which induces the M2 phenotype increasing CD163 and TGF-β1 expression. In DD kidneys, the TNF-α/NF-κB pathway could be involved in the increase of A2AR expression, which would activate the PKA–CREB axis, inducing the macrophage M2 phenotype, TGF-β1 production, and ultimately, fibrosis. Thus, in inflamed DD kidneys, an increase in A2AR expression is associated with the onset of fibrosis, which may contribute to graft dysfunction and prognostic differences between DD and LD transplants.

scholarly journals The striatal-enriched protein Rhes is a critical modulator of cocaine-induced molecular and behavioral responses

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Francesco Napolitano ◽  
Arianna De Rosa ◽  
Rosita Russo ◽  
Anna Di Maio ◽  
Martina Garofalo ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Dopaminergic System ◽  
Cocaine Exposure ◽  
Proteomic Profiling ◽  
Dopaminergic Transmission ◽  
Midbrain Dopaminergic Neurons ◽  
Knockout Animals ◽  
Molecular Brake

Abstract Previous evidence pointed out a role for the striatal-enriched protein Rhes in modulating dopaminergic transmission. Based on the knowledge that cocaine induces both addiction and motor stimulation, through its ability to enhance dopaminergic signaling in the corpus striatum, we have now explored the involvement of Rhes in the effects associated with this psychostimulant. Our behavioral data showed that a lack of Rhes in knockout animals caused profound alterations in motor stimulation following cocaine exposure, eliciting a significant leftward shift in the dose-response curve and triggering a dramatic hyperactivity. We also found that Rhes modulated either short- or long-term motor sensitization induced by cocaine, since lack of this protein prevents both of them in mutants. Consistent with this in vivo observation, we found that lack of Rhes in mice caused a greater increase in striatal cocaine-dependent D1R/cAMP/PKA signaling, along with considerable enhancement of Arc, zif268, and Homer1 mRNA expression. We also documented that lack of Rhes in mice produced cocaine-related striatal alterations in proteomic profiling, with a differential expression of proteins clustering in calcium homeostasis and cytoskeletal protein binding categories. Despite dramatic striatal alterations associated to cocaine exposure, our data did not reveal any significant changes in midbrain dopaminergic neurons as a lack of Rhes did not affect: (i) DAT activity; (ii) D2R-dependent regulation of GIRK; and (iii) D2R-dependent regulation of dopamine release. Collectively, our results strengthen the view that Rhes acts as a pivotal physiological “molecular brake” for striatal dopaminergic system overactivation induced by psychostimulants, thus making this protein of interest in regulating the molecular mechanism underpinning cocaine-dependent motor stimulatory effects.

scholarly journals Glucocerebrosidase Gene Therapy Induces Alpha-Synuclein Clearance and Neuroprotection of Midbrain Dopaminergic Neurons in Mice and Macaques

2021 ◽  
Vol 22 (9) ◽  
pp. 4825
Author(s):  
Diego Sucunza ◽  
Alberto J. Rico ◽  
Elvira Roda ◽  
María Collantes ◽  
Gloria González-Aseguinolaza ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Dopaminergic Neurons ◽  
Disease Modeling ◽  
Viral Vector ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Vector Coding ◽  
Midbrain Dopaminergic Neurons ◽  
Gene Coding ◽  
Disease Modifying Treatment

Mutations in the GBA1 gene coding for glucocerebrosidase (GCase) are the main genetic risk factor for Parkinson’s disease (PD). Indeed, identifying reduced GCase activity as a common feature underlying the typical neuropathological signatures of PD—even when considering idiopathic forms of PD—has recently paved the way for designing novel strategies focused on enhancing GCase activity to reduce alpha-synuclein burden and preventing dopaminergic cell death. Here we have performed bilateral injections of a viral vector coding for the mutated form of alpha-synuclein (rAAV9-SynA53T) for disease modeling purposes, both in mice as well as in nonhuman primates (NHPs), further inducing a progressive neuronal death in the substantia nigra pars compacta (SNpc). Next, another vector coding for the GBA1 gene (rAAV9-GBA1) was unilaterally delivered in the SNpc of mice and NHPs one month after the initial insult, together with the contralateral delivery of an empty/null rAAV9 for control purposes. Obtained results showed that GCase enhancement reduced alpha-synuclein burden, leading to improved survival of dopaminergic neurons. Data reported here support using GCase gene therapy as a disease-modifying treatment for PD and related synucleinopathies, including idiopathic forms of these disorders.

scholarly journals Medicinal plants possessed anti-Parkinsonian effects with emphasis on their mechanisms of action

2021 ◽  
Vol 17 (1) ◽  
pp. 232-237
Author(s):  
Ali Esmail Al-Snafi
Keyword(s):  
Medicinal Plants ◽  
Dopaminergic Neurons ◽  
Mechanisms Of Action ◽  
Nigrostriatal System ◽  
Beneficial Effects ◽  
Resting Tremor ◽  
A2a Receptor ◽  
Neuroprotective Actions ◽  
Neuro Inflammation ◽  
Adenosine A2a

Parkinsonʼs disease is a progressive neurodegenerative dysfunction characterized by the loss of dopaminergic neurons of the nigrostriatal system. Dopamine is important to maintain normal movement patterns. The cardinal physical signs of the disease are distal resting tremor, rigidity, bradykinesia, and asymmetric onset. Treatment aims to improve these motor symptoms. Many medicinal plants possessed Parkinsonian effects by different mechanisms, included inhibition of α-synuclein condensation, reduction of oxidative stress and neuro-inflammation, increase of dopaminergic neurons survival, blockade of the adenosine A2A receptor and regulation of molecular pathways involved in neuronal survival such as MAPK, Nrf2, and NF-κB, thus exerted neuroprotective actions. In the present review, we highlight the medicinal plants with potential anti-Parkinsonian effects with discussing the mechanisms of their beneficial effects.

scholarly journals Differential robustness to specific potassium channel deletions in midbrain dopaminergic neurons

2019 ◽  
Author(s):  
Alexis Haddjeri-Hopkins ◽  
Béatrice Marqueze-Pouey ◽  
Monica Tapia ◽  
Fabien Tell ◽  
Marianne Amalric ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Potassium Channel ◽  
Dopaminergic Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Wild Type ◽  
Current Clamp ◽  
Compensatory Mechanisms ◽  
Knock Out ◽  
Midbrain Dopaminergic Neurons

AbstractQuantifying the level of robustness of neurons in ion channel knock-out (KO) mice depends on how exhaustively electrical phenotype is assessed. We characterized the variations in behavior and electrical phenotype of substantia nigra pars compacta (SNc) dopaminergic neurons in SK3 and Kv4.3 potassium channel KOs. SK3 and Kv4.3 KO mice exhibited a slight increase in exploratory behavior and impaired motor learning, respectively. Combining current-clamp characterization of 16 electrophysiological parameters and multivariate analysis, we found that the electrical phenotype of SK3 KO neurons was not different from wild-type neurons, while that of Kv4.3 KO neurons was significantly altered. Consistently, voltage-clamp recordings of the underlying currents demonstrated that the SK current charge was unchanged in SK3 KO neurons while the Kv4-mediated A-type current was virtually abolished in Kv4.3 KO neurons. We conclude that the robustness of SNc dopaminergic neurons to potassium channel deletions is highly variable, due to channel-specific compensatory mechanisms.

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