Pimavanserin Promotes Trophic Factor Release and Protects Cultured Primary Dopaminergic Neurons Exposed to MPP+ in a GDNF-Dependent Manner

Abstractα-Synuclein is critical in the pathogenesis of Parkinson’s disease and related disorders, yet it remains unclear how its aggregation causes degeneration of human dopaminergic neurons. In this study, we induced α-synuclein aggregation in human iPSC-derived dopaminergic neurons using fibrils generated de novo or amplified in the presence of brain homogenates from Parkinson’s disease or multiple system atrophy. Increased α-synuclein monomer levels promote seeded aggregation in a dose and time-dependent manner, which is associated with a further increase in α-synuclein gene expression. Progressive neuronal death is observed with brain-amplified fibrils and reversed by reduction of intraneuronal α-synuclein abundance. We identified 56 proteins differentially interacting with aggregates triggered by brain-amplified fibrils, including evasion of Parkinson’s disease-associated deglycase DJ-1. Knockout of DJ-1 in iPSC-derived dopaminergic neurons enhance fibril-induced aggregation and neuronal death. Taken together, our results show that the toxicity of α-synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our study demonstrates how Parkinson’s disease-associated genes influence the phenotypic manifestation of strains in human neurons.

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Activation of the Akt1-CREB pathway promotes RNF146 expression to inhibit PARP1-mediated neuronal death

Science Signaling ◽

10.1126/scisignal.aax7119 ◽

2020 ◽

Vol 13 (663) ◽

pp. eaax7119

Author(s):

Hyojung Kim ◽

Jisoo Park ◽

Hojin Kang ◽

Seung Pil Yun ◽

Yun-Song Lee ◽

...

Keyword(s):

Chlorogenic Acid ◽

Transcriptional Activation ◽

Dopaminergic Neurons ◽

Cultured Cells ◽

Intraperitoneal Administration ◽

Neuronal Loss ◽

Postmortem Brain ◽

Dependent Manner ◽

Gene Encoding ◽

Creb Pathway

Progressive degeneration of dopaminergic neurons characterizes Parkinson’s disease (PD). This neuronal loss occurs through diverse mechanisms, including a form of programmed cell death dependent on poly(ADP-ribose) polymerase-1 (PARP1) called parthanatos. Deficient activity of the kinase Akt1 and aggregation of the protein α-synuclein are also implicated in disease pathogenesis. Here, we found that Akt1 suppressed parthanatos in dopaminergic neurons through a transcriptional mechanism. Overexpressing constitutively active Akt1 in SH-SY5Y cells or culturing cells with chlorogenic acid (a polyphenol found in coffee that activates Akt1) stimulated the CREB-dependent transcriptional activation of the gene encoding the E3 ubiquitin ligase RNF146. RNF146 inhibited PARP1 not through its E3 ligase function but rather by binding to and sequestering PAR, which enhanced the survival of cultured cells exposed to the dopaminergic neuronal toxin 6-OHDA or α-synuclein aggregation. In mice, intraperitoneal administration of chlorogenic acid activated the Akt1-CREB-RNF146 pathway in the brain and provided neuroprotection against both 6-OHDA and combinatorial α-synucleinopathy in an RNF146-dependent manner. Furthermore, dysregulation of the Akt1-CREB pathway was observed in postmortem brain samples from patients with PD. The findings suggest that therapeutic restoration of RNF146 expression, such as by activating the Akt1-CREB pathway, might halt neurodegeneration in PD.

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Ibogaine Modifies GDNF, BDNF and NGF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits

10.26434/chemrxiv.7261559 ◽

2018 ◽

Author(s):

Soledad Marton ◽

Bruno González ◽

Sebastián Rodríguez ◽

Ernesto Miquel ◽

Laura Martínez Palma ◽

...

Keyword(s):

Neurotrophic Factor ◽

Dopaminergic Neurons ◽

Brain Regions ◽

Dopamine Neurons ◽

Acute Administration ◽

Dependent Manner ◽

Self Administration ◽

Seeking Behavior ◽

A Site ◽

Dose Dependent

Ibogaine is a psychedelic alkaloid which has been subject of intense scientific research due to its reported ability to attenuate drug-seeking behavior. Recent work suggested that ibogaine effects on alcohol self-administration in rats was related to the release of Glial Cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts soma of dopamine neurons. It is well known that neurotrophic factors (NFs) mediate the neuroadaptations induced in the mesocorticolimbic dopaminergic system by repeated exposure to drugs. Although previous reports have shown ibogaine´s ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF, Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Thus, rats were i.p. treated with ibogaine 20 mg/kg (I20), 40 mg/kg (I40) or vehicle, and NFs expression was analyzed after 3 and 24 hours. Only at 24 h an increase of the expression for the three NFs were observed in a site and dose dependent manner. Results for GDNF showed that only I40 selectively upregulated its expression in the VTA and SN. Both doses of ibogaine elicited a large increase in the expression of BDNF in the NAcc, SN and PFC, while a significant effect was found in the VTA only for I40. Finally, NGF was found to be upregulated in all regions after I40, while a selective upregulation was found in PFC and VTA for the I20 treatment. An increase in the content of mature GDNF was observed in the VTA but no significant increase in the mature BDNF protein content was found in all the studied areas. Interestingly, an increase in the content of proBDNF was detected in the NAcc for both treatments. Further research is needed to understand the neurochemical bases of these changes, and to confirm their contribution to the anti-addictive properties of ibogaine.

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Catecholaminergic neurons supplying the hindgut of the crayfish Procambarus clarkii

Canadian Journal of Zoology ◽

10.1139/z91-391 ◽

1991 ◽

Vol 69 (11) ◽

pp. 2778-2785 ◽

Cited By ~ 22

Author(s):

A. Joffre Mercier ◽

Ian Orchard ◽

Arthur Schmoeckel

Keyword(s):

Dopaminergic Neurons ◽

High Performance ◽

Procambarus Clarkii ◽

Dependent Manner ◽

Catecholamine Biosynthesis ◽

Catecholaminergic Neurons ◽

Rate Limiting Step ◽

Single Axon ◽

Rate Limiting ◽

Dose Dependent

The crayfish hindgut is surrounded by a dense plexus of nerve terminals which are known to contain catecholamines. This plexus is positively stained using a monoclonal antibody to tyrosine hydroxylase, the enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis. Two immunoreactive neurons, whose cell bodies are located in the third and fourth abdominal ganglia, contribute to the nerve plexus. Each of these neurons sends a single axon posteriorly through the ventral nerve cord and into the intestinal nerve, where the axon bifurcates to supply the anterior and posterior hindgut regions. High-performance liquid chromatography, coupled to electrochemical detection, demonstrates the presence of dopamine in the intestinal nerve of Procambarus clarkii. Dopamine increases the motility of the isolated hindgut in a dose-dependent manner. The results suggest that two dopaminergic neurons are involved in the neurogenic coordination of hindgut movements.

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Neurturin Evokes MAPK-Dependent Upregulation of Egr4 and KCC2 in Developing Neurons

Neural Plasticity ◽

10.1155/2011/641248 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Anastasia Ludwig ◽

Pavel Uvarov ◽

Christophe Pellegrino ◽

Judith Thomas-Crusells ◽

Sebastian Schuchmann ◽

...

Keyword(s):

Transcription Factor ◽

Crucial Role ◽

Trophic Factor ◽

Dependent Manner ◽

Functional Development ◽

Immature Neurons ◽

Intracellular Pathways ◽

Developing Neurons

The K-Cl cotransporter KCC2 plays a crucial role in the functional development ofGABAA-mediated responses rendering GABA hyperpolarizing in adult neurons. We have previously shown that BDNF upregulates KCC2 in immature neurons through the transcription factor Egr4. The effect of BDNF on Egr4 and KCC2 was shown to be dependent on the activation of ERK1/2. Here we demonstrate that the trophic factor neurturin can also trigger Egr4 expression and upregulate KCC2 in an ERK1/2-dependent manner. These results show that Egr4 is an important component in the mechanism for trophic factor-mediated upregulation of KCC2 in immature neurons involving the activation of specific intracellular pathways common to BDNF and Neurturin.

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Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis

Cell Death and Disease ◽

10.1038/s41419-020-03369-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jian-Jun Guo ◽

Feng Yue ◽

Dong-Yan Song ◽

Luc Bousset ◽

Xin Liang ◽

...

Keyword(s):

Substantia Nigra ◽

Dopaminergic Neurons ◽

Cellular Response ◽

Macaca Fascicularis ◽

Brain Regions ◽

Cellular Level ◽

Pathological Process ◽

Iron Deposition ◽

Dependent Manner ◽

Axonal Swelling

AbstractIron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.

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Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1909814117 ◽

2020 ◽

Vol 117 (8) ◽

pp. 4281-4291 ◽

Cited By ~ 9

Author(s):

Su Jin Ham ◽

Daewon Lee ◽

Heesuk Yoo ◽

Kyoungho Jun ◽

Heejin Shin ◽

...

Keyword(s):

Parkinson Disease ◽

Missense Mutation ◽

Dopaminergic Neurons ◽

Calcium Uptake ◽

Mitochondrial Calcium ◽

Dependent Manner ◽

Mitochondrial Calcium Uniporter ◽

Calcium Uniporter ◽

Mitochondrial Calcium Uptake ◽

Transgenic Flies

VDAC1 is a critical substrate of Parkin responsible for the regulation of mitophagy and apoptosis. Here, we demonstrate that VDAC1 can be either mono- or polyubiquitinated by Parkin in a PINK1-dependent manner. VDAC1 deficient with polyubiquitination (VDAC1 Poly-KR) hampers mitophagy, but VDAC1 deficient with monoubiquitination (VDAC1 K274R) promotes apoptosis by augmenting the mitochondrial calcium uptake through the mitochondrial calcium uniporter (MCU) channel. The transgenic flies expressing Drosophila Porin K273R, corresponding to human VDAC1 K274R, show Parkinson disease (PD)-related phenotypes including locomotive dysfunction and degenerated dopaminergic neurons, which are relieved by suppressing MCU and mitochondrial calcium uptake. To further confirm the relevance of our findings in PD, we identify a missense mutation of Parkin discovered in PD patients, T415N, which lacks the ability to induce VDAC1 monoubiquitination but still maintains polyubiquitination. Interestingly, Drosophila Parkin T433N, corresponding to human Parkin T415N, fails to rescue the PD-related phenotypes of Parkin-null flies. Taken together, our results suggest that VDAC1 monoubiquitination plays important roles in the pathologies of PD by controlling apoptosis.

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Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin

The Journal of Cell Biology ◽

10.1083/jcb.201009136 ◽

2011 ◽

Vol 192 (1) ◽

pp. 153-169 ◽

Cited By ~ 110

Author(s):

Maxim M. Bespalov ◽

Yulia A. Sidorova ◽

Sarka Tumova ◽

Anni Ahonen-Bishopp ◽

Ana Cathia Magalhães ◽

...

Keyword(s):

Heparan Sulfate ◽

Receptor Tyrosine Kinase ◽

Cortical Neurons ◽

Dopaminergic Neurons ◽

Therapeutic Potential ◽

Aminobutyric Acid ◽

Dependent Manner ◽

Kinase Activation ◽

Matrix Bound ◽

Immobilized Matrix

Glial cell line–derived neurotrophic factor (GDNF) family ligands (GFLs) are potent survival factors for dopaminergic neurons and motoneurons with therapeutic potential for Parkinson’s disease. Soluble GFLs bind to a ligand-specific glycosylphosphatidylinositol-anchored coreceptor (GDNF family receptor α) and signal through the receptor tyrosine kinase RET. In this paper, we show that all immobilized matrix-bound GFLs, except persephin, use a fundamentally different receptor. They interact with syndecan-3, a transmembrane heparan sulfate (HS) proteoglycan, by binding to its HS chains with high affinity. GFL–syndecan-3 interaction mediates both cell spreading and neurite outgrowth with the involvement of Src kinase activation. GDNF promotes migration of cortical neurons in a syndecan-3–dependent manner, and in agreement, mice lacking syndecan-3 or GDNF have a reduced number of cortical γ-aminobutyric acid–releasing neurons, suggesting a central role for the two molecules in cortical development. Collectively, syndecan-3 may directly transduce GFL signals or serve as a coreceptor, presenting GFLs to the signaling receptor RET.

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Effects of Antiplatelet and Nonsteroidal Anti-inflammatory Medications on Platelet-Rich Plasma: A Systematic Review

Orthopaedic Journal of Sports Medicine ◽

10.1177/2325967120912841 ◽

2020 ◽

Vol 8 (4) ◽

pp. 232596712091284 ◽

Cited By ~ 1

Author(s):

Christopher Frey ◽

Peter Chia Yeh ◽

Prathap Jayaram

Keyword(s):

Systematic Review ◽

Growth Factors ◽

Growth Factor ◽

Platelet Rich Plasma ◽

Antiplatelet Agent ◽

Cochrane Library ◽

Dependent Manner ◽

Growth Factor Release ◽

Anti Inflammatory ◽

Factor Release

Background: Platelet-rich plasma (PRP) has wide applications in orthopaedic care. Its beneficial effects are attributed to the growth factor profile from the platelet secretome. In theory, these effects would be diminished by medications that inhibit platelet activation and/or the subsequent release of growth factors. Purpose: To determine whether commonly used antiplatelets, nonsteroidal anti-inflammatory drugs (NSAIDs), or anticoagulant medications affect platelet growth factor release in PRP. Study Design: Systematic review; Level of evidence, 2. Method: A systematic review of the literature related to antiplatelet, anti-inflammatory, and anticoagulant drugs was performed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We used the Downs and Black objective quality scoring system. The literature search consisted of PubMed and Cochrane Library databases. Search terms consisted of 1 item selected from “platelet-rich plasma,” “platelet-derived growth factor,” and “platelet-rich plasma AND growth factor” combined with 1 item from “antiplatelet,” “aspirin,” “anticoagulant,” and “NSAID.” Only studies published within the past 25 years were included. Results: A total of 15 studies met the inclusion criteria: 7 studies detected no significant decrease in growth factors or mitogenesis, whereas 6 detected a decrease with antiplatelet agents, 1 detected mixed results with an antiplatelet agent, and 1 had mixed results with an antiplatelet agent/vasodilator. In terms of PRP activation, all 3 studies assessing collagen, the 2 studies analyzing adenosine diphosphate alone, and the 1 study investigating arachidonic acid found a decrease in growth factor concentration. Conclusion: Antiplatelet medications may decrease the growth factor release profile in a cyclooxygenase 1– and cyclooxygenase 2–dependent manner. Eight of 15 studies found a decrease in growth factors or mitogenesis. However, more studies are needed to comprehensively understand antiplatelet effects on the PRP secretome.

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