Denis Soulet

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Effect of sex and gonadectomy on brain MPTP toxicity and response to dutasteride treatment in mice

Neuropharmacology

Mitotic phosphotyrosine network analysis reveals that tyrosine phosphorylation regulates Polo-like kinase 1 (PLK1)

Science signaling, Jan 13, 2016

Tyrosine phosphorylation is closely associated with cell proliferation. During the cell cycle, se... more Tyrosine phosphorylation is closely associated with cell proliferation. During the cell cycle, serine and threonine phosphorylation plays the leading role, and such phosphorylation events are most dynamic during the mitotic phase of the cell cycle. However, mitotic phosphotyrosine is not well characterized. Although a few functionally-relevant mitotic phosphotyrosine sites have been characterized, evidence suggests that this modification may be more prevalent than previously appreciated. Here, we examined tyrosine phosphorylation in mitotic human cells including those on spindle-associated proteins.? Database mining confirmed ~2000 mitotic phosphotyrosine sites, and network analysis revealed a number of subnetworks that were enriched in tyrosine-phosphorylated proteins, including components of the kinetochore or spindle and SRC family kinases. We identified Polo-like kinase 1 (PLK1), a major signaling hub in the spindle subnetwork, as phosphorylated at the conserved Tyr(217) in the ...

Gastrointestinal Dysfunctions in Parkinson’s Disease: Symptoms and Treatments

Parkinson's Disease, 2016

A diagnosis of Parkinson’s disease is classically established after the manifestation of motor sy... more A diagnosis of Parkinson’s disease is classically established after the manifestation of motor symptoms such as rigidity, bradykinesia, and tremor. However, a growing body of evidence supports the hypothesis that nonmotor symptoms, especially gastrointestinal dysfunctions, could be considered as early biomarkers since they are ubiquitously found among confirmed patients and occur much earlier than their motor manifestations. According to Braak’s hypothesis, the disease is postulated to originate in the intestine and then spread to the brain via the vagus nerve, a phenomenon that would involve other neuronal types than the well-established dopaminergic population. It has therefore been proposed that peripheral nondopaminergic impairments might precede the alteration of dopaminergic neurons in the central nervous system and, ultimately, the emergence of motor symptoms. Considering the growing interest in the gut-brain axis in Parkinson’s disease, this review aims at providing a compre...

Neuroprotective and immunomodulatory effects of raloxifene in the myenteric Plexus of a mouse model of Parkinson’s disease

Neurobiology of Aging, 2016

Motor symptoms in Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;a... more Motor symptoms in Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD) are often preceded by nonmotor symptoms related to dysfunctions of the autonomic nervous system such as constipation, defecatory problems, and delayed gastric emptying. These gastrointestinal impairments are associated with the alteration of dopaminergic (DAergic) neurons in the myenteric plexus of the gut. Recently, we demonstrated the anti-inflammatory properties of estrogens to treat intestinal neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The present study aimed to investigate the neuroprotective and anti-inflammatory roles of raloxifene, a selective estrogen receptor modulator (SERM) already commercialized for osteoporosis treatment. In MPTP-treated mice, we found that raloxifene decreased the loss of DAergic neurons and prevented the increase in proinflammatory macrophage density in the myenteric plexus. Interestingly, raloxifene activity was prevented by the G protein-coupled estrogen receptor 1 (GPER1) antagonist G15, suggesting that raloxifene effects were mainly mediated by GPER1. Moreover, monocytic cell proinflammatory polarization, nuclear factor-kappa B (NF-κB) response, nitric oxide (NO), and proinflammatory cytokines production following 1-methyl-4-phenylpyridinium (MPP(+)) treatment were also prevented by raloxifene in vitro. Overall, the present results suggest that raloxifene may help preventing the loss of DAergic neurons in the myenteric plexus in an MPTP mouse model of PD, at least in part through its anti-inflammatory effects. This suggests that drug repurposing of raloxifene might represent a promising therapeutic avenue to prevent systemic inflammation and peripheral neuronal dysfunction at early PD stages.

Perspective: How to Make Microarray, Serial Analysis of Gene Expression, and Proteomic Relevant to Day-to-Day Endocrine Problems and Physiological Systems

Endocrinology, Jul 1, 2013

... Perspective: How to Make Microarray, Serial Analysis of Gene Expression, and Proteomic Releva... more

Role of endocytosis in the internalization of spermidine-C2-BODIPY, a highly fluorescent probe of polyamine transport

Biochem J, 2002

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Organotypic Explant Culture of Glioblastoma Multiforme and Subsequent Single‐Cell Suspension

Current Protocols in Stem Cell Biology, Dec 1, 2011

Glioblastoma multiforme (GBM) is one of the most aggressive brain tumors. GBM cell lines used in ... more Glioblastoma multiforme (GBM) is one of the most aggressive brain tumors. GBM cell lines used in laboratory studies are frequently passaged in various culture media at high proliferation rates, resulting in significant genetic and molecular alterations. Thus, data obtained in cell lines are often inapplicable to patient tumors. Furthermore, recent studies suggest that there is a stem cell-like hierarchy among GBM cell populations and a crucial role for tumor vasculature in stem cells, as well as tumor growth, which cannot be reproduced in cell line cultures. Our laboratory has developed a novel three-dimensional (3D) organotypic &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;explant&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; system of surgical GBM specimens that preserves tumor cells in their original milieu, as well as the cytoarchitecture of the tumor stroma. Our previous study on the role of Notch inhibition has demonstrated a definitive effect on the tumor endothelium that could only be highlighted by this system. In this unit, we describe a detailed protocol for preparing GBM explants, and discuss strengths, as well as limitations of the explant system as an in vitro 3D model of GBM.

Mutant huntingtin interacts with {beta}-tubulin and disrupts vesicular transport and insulin secretion

Human Molecular Genetics, 2009

Huntington's disease is a severe progressive neurodegenerative disorder caused by a CAG expansion... more Huntington's disease is a severe progressive neurodegenerative disorder caused by a CAG expansion in the IT15 gene, which encodes huntingtin. The disease primarily affects the neostriatum and cerebral cortex and also associates with increased incidence of diabetes. Here, we show that mutant huntingtin disrupts intracellular transport and insulin secretion by direct interference with microtubular b-tubulin. We demonstrate that mutant huntingtin impairs glucose-stimulated insulin secretion in insulin-producing b-cells, without altering stored levels of insulin. Using VSVG-YFP, we show that mutant huntingtin retards post-Golgi transport. Moreover, we demonstrate that the speed of insulin vesicle trafficking is reduced. Using immunoprecipitation of mutant and wild-type huntingtin in combination with mass spectrometry, we reveal an enhanced and aberrant interaction between mutant huntingtin and b-tubulin, implying the underlying mechanism of impaired intracellular transport. Thus, our findings have revealed a novel pathogenetic process by which mutant huntingtin may disrupt hormone exocytosis from b-cells and possibly impair vesicular transport in any cell that expresses the pathogenic protein.

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Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications

Brain a Journal of Neurology, Jan 28, 2011

Cell therapy offers the possibility of replacing degenerated neurons thereby improving the sympto... more Cell therapy offers the possibility of replacing degenerated neurons thereby improving the symptoms of neurodegenerative disorders such as Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. However, clinical benefits in patients with Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease, if any, have been transient and modest. Grafts survived well at 18 months in one patient with Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease, but graft survival was markedly attenuated by 10 years in three other patients from this transplantation cohort. It is critical to delineate the causes of graft degeneration if such therapies will be utilized in patients with a goal of achieving meaningful clinical benefit. Similar challenges may also accrue to future stem cell therapies. Here we discuss the potential causes of suboptimal long-term graft survival in patients with Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease, including allograft immunoreactivity, microglial responses targeted to grafted cells and cell-to-cell neurotoxicity. We also discuss similar challenges and unique differences comparing neuronal grafts in patients with Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s and Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s diseases.

Bone-marrow-derived microglia: myth or reality?

Current Opinion in Pharmacology, 2008

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GPER1-mediated immunomodulation and neuroprotection in the myenteric plexus of a mouse model of Parkinson's disease

Neurobiology of Disease, 2015

Lewy pathology affects the gastrointestinal tract in Parkinson&amp;amp;amp;amp;amp;amp;amp;am... more Lewy pathology affects the gastrointestinal tract in Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD) and recent reports suggest a link between the disorder and gut inflammation. In this study, we investigated enteric neuroprotection and macrophage immunomodulation by 17β-estradiol (E2) and the G protein-coupled estrogen receptor 1 (GPER1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model. We found that both E2 and the GPER1 agonist G1 are protective against the loss of dopamine myenteric neurons and inhibited enteric macrophage infiltration in MPTP-treated mice. Coadministration of GPER1 antagonist G15, while completely blocking the neuroprotective and anti-inflammatory effects of G1 also partially prevented those of E2. Interestingly, we found that E2 and G1 treatments could directly alter MPTP-mediated immune responses independently from neurodegenerative processes. Analyses of monocyte/macrophage NF-κB and iNOS activation and FACs immunophenotype indicated that 1-methyl-4-phenylpyridinium (MPP(+)) treatment induces a strong immune response in monocytes, comparable to that of canonical challenge by lipopolysaccharide. In these cells, G1 and E2 treatment are equally potent in promoting a shift toward an anti-inflammatory &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;M2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; immunophenotype reducing MPP(+)-induced NF-κB and iNOS activation. Moreover, G15 also antagonized the immunomodulatory effects of G1 in MPP(+)-treated macrophages. Together these data provide the first evidence for the role of GPER1 in enteric immunomodulation and neuroprotection. Considering increasing recognition for myenteric pathology as an early biomarker for PD, these findings provide a valuable contribution for better understanding and targeting of future therapeutic strategies.

Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A 2 -IIA

Proceedings of the National Academy of Sciences, 2015

Platelets are anucleated blood elements highly potent at generating extracellular vesicles (EVs) ... more Platelets are anucleated blood elements highly potent at generating extracellular vesicles (EVs) called microparticles (MPs). Whereas EVs are accepted as an important means of intercellular communication, the mechanisms underlying platelet MP internalization in recipient cells are poorly understood. Our lipidomic analyses identified 12(S)-hydroxyeicosatetranoic acid [12(S)-HETE] as the predominant eicosanoid generated by MPs. Mechanistically, 12(S)-HETE is produced through the concerted activity of secreted phospholipase A2 IIA (sPLA2-IIA), present in inflammatory fluids, and platelet-type 12-lipoxygenase (12-LO), expressed by platelet MPs. Platelet MPs convey an elaborate set of transcription factors and nucleic acids, and contain mitochondria. We observed that MPs and their cargo are internalized by activated neutrophils in the endomembrane system via 12(S)-HETE. Platelet MPs are found inside neutrophils isolated from the joints of arthritic patients, and are found in neutrophils ...

Automated High Performance Analysis of Lung Morphometry

American Journal of Respiratory Cell and Molecular Biology, 2015

Automation of lung morphometric analysis is an asset in the study of lung pathophysiology because... more Automation of lung morphometric analysis is an asset in the study of lung pathophysiology because it is an assurance of robustness, reproducibility and rapidity. The novel automated morphometric approach presented here meets these criteria. This new method collects multiple parameters allowing quantitative elucidation of the pathophysiology of the developing and mature lungs. The automated morphometric analysis is reliable and allows the analysis of a greater proportion of each lung together with a higher number of samples and superior reproducibility than manual analysis. The use of this method revealed that treatment with 80% oxygen and lung development presented an opposite effect on most of the analyzed parameters. In conclusion, this novel approach allowed the collection of new fundamental morphometric data on lung development and a deeper comprehension of the effect of hyperoxia.

Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation

Blood, Jan 2, 2014

Mitochondrial DNA (mtDNA) is a highly potent inflammatory trigger and is reportedly found outside... more Mitochondrial DNA (mtDNA) is a highly potent inflammatory trigger and is reportedly found outside the cells in blood in various pathologies. Platelets are abundant in blood where they promote hemostasis. Although lacking a nucleus, platelets contain functional mitochondria. On activation, platelets produce extracellular vesicles known as microparticles. We hypothesized that activated platelets could also release their mitochondria. We show that activated platelets release respiratory-competent mitochondria, both within membrane-encapsulated microparticles and as free organelles. Extracellular mitochondria are found in platelet concentrates used for transfusion and are present at higher levels in those that induced acute reactions (febrile nonhemolytic reactions, skin manifestations, and cardiovascular events) in transfused patients. We establish that the mitochondrion is an endogenous substrate of secreted phospholipase A2 IIA (sPLA2-IIA), a phospholipase otherwise specific for bact...

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Role of Polyamines in the Control of the Immune Response in the Brain

Polyamine Cell Signaling, 2006

Polyamines are essential polycations involved in a large variety of biological functions, includi... more Polyamines are essential polycations involved in a large variety of biological functions, including modulation of the nucleic acid conformation, RNA export and their degradation, protein synthesis, eIF-5A posttranslational modification, signal transduction, cell growth and differentiation, and tumor progression ( 1 –bi3. These various aspects in the biology of polyamines are addressed in other sections of this book.

Disrupts Vesicular Transport and Insulin Secretion

Evidence for a Multistep Model for Eukaryotic Polyamine Transport

Polyamine Cell Signaling, 2006

1. Introduction One of the most intriguing aspects of polyamine biology is the considerable diver... more

Extracellular Na+ levels regulate formation and activity of the NaX/alpha1-Na+/K+-ATPase complex in neuronal cells

Frontiers in Cellular Neuroscience, 2014

MnPO neurons play a critical role in hydromineral homeostasis regulation by acting as sensors of ... more MnPO neurons play a critical role in hydromineral homeostasis regulation by acting as sensors of extracellular sodium concentration ([Na(+)]out). The mechanism underlying Na(+)-sensing involves Na(+)-flow through the NaX channel, directly regulated by the Na(+)/K(+)-ATPase α1-isoform which controls Na(+)-influx by modulating channel permeability. Together, these two partners form a complex involved in the regulation of intracellular sodium ([Na(+)]in). Here we aim to determine whether environmental changes in Na(+) could actively modulate the NaX/Na(+)/K(+)-ATPase complex activity. We investigated the complex activity using patch-clamp recordings from rat MnPO neurons and Neuro2a cells. When the rats were fed with a high-salt-diet, or the [Na(+)] in the culture medium was increased, the activity of the complex was up-regulated. In contrast, drop in environmental [Na(+)] decreased the activity of the complex. Interestingly under hypernatremic condition, the colocalization rate and protein level of both partners were up-regulated. Under hyponatremic condition, only NaX protein expression was increased and the level of NaX/Na(+)/K(+)-ATPase remained unaltered. This unbalance between NaX and Na(+)/K(+)-ATPase pump proportion would induce a bigger portion of Na(+)/K(+)-ATPase-control-free NaX channel. Thus, we suggest that hypernatremic environment increases NaX/Na(+)/K(+)-ATPase α1-isoform activity by increasing the number of both partners and their colocalization rate, whereas hyponatremic environment down-regulates complex activity via a decrease in the relative number of NaX channels controlled by the pump.

Ornithine metabolism along the female mouse nephron: localization of ornithine decarboxylase and ornithine aminotransferase

Pflügers Archiv, 2000

The fate of ornithine in the nephron of the female OF-1 Swiss mouse remains unknown. The aim of t... more The fate of ornithine in the nephron of the female OF-1 Swiss mouse remains unknown. The aim of the present study was to identify the nephron segments containing the key enzymes involved in ornithine metabolism: ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT). Viable tubules isolated by microdissection were incubated with [1-14C]ornithine to study the oxidative pathway. Other tubules were permeabilized to measure the ODC activity. Ornithine was decarboxylated in all intact tubules. Gabaculine, a suicide inhibitor of OAT, and rotenone sharply decreased the production of 14CO2 from [1-14C]ornithine. No ODC activity was found in permeabilized tubules isolated from untreated mice. Testosterone increased ODC activity in the proximal tubule substantially and to a minor extent in other nephron segments. In situ hybridization showed ODC messenger ribonucleic acid (mRNA) to be absent in kidneys of untreated females but abundant in the cortex and the outer stripe of the outer medulla of testosterone-treated female mice. The whole proximal tubule contained a great density of silver grains corresponding to ODC mRNA. In conclusion, no basal ODC activity was found in the nephron of female mice. The testosterone-inducible ODC is localized mainly in the proximal tubule, but is also present in distal tubules and collecting ducts. OAT is distributed along the whole nephron, but its activity is higher in proximal tubules than in distal tubules.

Critical issues of clinical human embryonic stem cell therapy for brain repair

Trends in Neurosciences, 2008

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