Biomedical subjects

Philippe Vernier

Publications and source records attributed to Philippe Vernier.

At least 19 recordsLinked to original sources

PubMed2006

Androgen-dependent stimulation of brain dopaminergic systems in the female European eel (Anguilla anguilla).

Dopamine (DA), a neurotransmitter present in all vertebrates, is involved in processes such as motor function, learning and behavior, sensory activities, and neuroendocrine control of pituitary hormone release. In the female eel, we analyzed how gonadal steroids regulate brain expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in the biosynthesis of DA. TH mRNA levels were assayed by quantitative real-time RT-PCR. TH-positive nuclei were also localized by in situ hybridization (ISH) and immunohistochemistry, and the location of TH nuclei that project to the pituitary was determined using 1,1'-dioctadecyl-3,3,3',3'-tetramethylindicarbocyanine perchlorate retrograde tracing. Chronic in vivo treatment with testosterone increased TH mRNA specifically in the periglomerular area of the olfactory bulbs and in the nucleus preopticus anteroventralis (NPOav). NPOav was labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindicarbocyanine perchlorate, showing that this nucleus is hypophysiotropic in the eel. The nonaromatizable 5alpha-dihydrotestosterone gave identical results in both areas, whereas 17beta-estradiol had no stimulatory effect, showing that the observed stimulatory effects of testosterone were androgen dependent. In teleosts, DA neurons originating from the NPOav directly inhibit gonadotropic function, and our results indicate an androgen-dependent, positive feedback on this neuroendocrine control in the eel. In mammals, DA interneurons in the olfactory bulbs are involved in the enhancement of olfactory sensitivity and discrimination. Our results in the European eel suggest an androgen-dependent stimulation of olfactory processing, a sensory function believed to be important in eel navigation during its reproductive migration toward the oceanic spawning grounds. To our knowledge, this is the first evidence from any vertebrate of an androgen-dependent effect on DAergic activity in the olfactory bulbs, providing a new basis for understanding the regulation by gonadal steroids of central DAergic systems in vertebrates.

Anguilla↗

PubMed2006

A phylotypic stage in vertebrate brain development: GABA cell patterns in zebrafish compared with mouse.

A recent comparison of early forebrain gene expression in mouse and zebrafish revealed highly comparable expression patterns of developmentally relevant genes, for example, of proneural (Neurogenin1, NeuroD, Mash1/Zash1a) genes involved in neurogenesis at a particular time window (mouse: embryonic day 12.5/13.5; zebrafish: 3 days). Here we extend this analysis to the description of gamma-aminobutyric acid (GABA) cell patterns in the early postembryonic zebrafish brain (i.e., during early secondary neurogenesis). We find again an astonishing degree of correspondences of GABA cell patterns between zebrafish and mouse during this previously established critical time window, for example, regarding absence of GABA cells in certain forebrain regions (pallium, dorsal thalamus, eminentia thalami) or with respect to the spatiotemporal occurrence of GABA cells (e.g., late cerebellar GABA cells). Furthermore, there is perfect correlation with previously established proneural gene expression patterns (i.e., absence of Mash1/Zash1a gene expression in GABA-cell-free forebrain regions) between mouse and zebrafish. The available information in additional vertebrate species, especially in Xenopus, is also highly consistent with our analysis here and suggests that a "phylotypic stage" of neurogenesis during vertebrate brain development may be present.

Animals↗

PubMed2006

Morphological and gene expression similarities suggest that the ascidian neural gland may be osmoregulatory and homologous to vertebrate peri-ventricular organs.

Summary The central nervous system (cerebral ganglion) of adult ascidians is linked to the neural gland complex (NGC), which consists of a dorsal tubercle, a ciliated duct and a neural gland. The function of the NGC has been the subject of much debate. The recent publication of the complete genomic sequence of Ciona intestinalis provides new opportunities to examine the presence and distribution of protein families in this basal chordate. We focus here on the ascidian neuropeptide G-protein-coupled receptors (GPCRs), the vertebrate homologues of which are involved in homeostasis. In situ hybridization revealed that five Ciona GPCRs [vasopressin receptor, somatostatin receptor, CRH (corticotropin-releasing hormone) receptor, angiotensin receptor and tachykinin receptor] are expressed in the NGC of adult ascidians. These findings, together with histological and ultrastructural data, provide evidence to support a role for the ascidian NGC in maintaining ionic homeostasis. We further speculate about the potential similarities between the ascidian NGC and the vertebrate choroid plexus, a neural peri-ventricular organ.

Animals↗

PubMed2005

Secondary neurogenesis in the brain of the African clawed frog, Xenopus laevis, as revealed by PCNA, Delta-1, Neurogenin-related-1, and NeuroD expression.

After primary neurogenesis in the Xenopus laevis embryo, a massive new surge of neurogenesis and related neurogenic and proneural gene expression occurs in the spinal cord at the beginning of the larval period (starting at Stage 46), which corresponds to well-documented secondary neurogenesis in larval zebrafish central nervous system development. Here, we document related neural proliferation and gene expression patterns in the brain of Xenopus, in various embryonic and larval stages, showing the distribution of proliferative cells (immunostaining of cells containing the proliferating cell nuclear antigen; the auxiliary protein of DNA polymerase delta; PCNA), and the activity of some critical genes expressed during neurogenesis (i.e., Delta-1, Neurogenin-related-1, NeuroD). This study reveals that the early larval stage in Xenopus (Stage 48) displays patterns of proliferation (PCNA), as well as of neurogenic (Delta-1) and proneural (Ngnr-1; NeuroD) gene expression that are qualitatively almost identical to those seen in the 3-day postembryonic zebrafish or the 12.5/13.5-day embryonic mouse. Furthermore, a comparable bauplan of early proliferation zones (including their neuromeric organization) as described in the postembryonic zebrafish apparently exists in tetrapods (Xenopus). Altogether, the data presented suggest a common brain bauplan on the level of early proliferation patterns and neurogenic/proneural gene activity in anamniotes, if not vertebrates.

Animals↗

PubMed2005

A quantitative real-time RT-PCR assay for European eel tyrosine hydroxylase.

Dopamine (DA) plays a key inhibitory role in pubertal development of the European eel, but how DAergic neuronal activity is regulated is not known in this species. In order to investigate the regulation of DA inhibition at the molecular level, we developed a quantitative real-time RT-PCR (qrtRT-PCR) assay, using the Light Cycler system, for the expression of eel tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. Two different reference genes were compared: the previously cloned eel cytochrome b, and eel acidic ribosomal phosphoprotein P0, the latter of which we cloned and partly sequenced. To further validate the assay, different methods of total RNA extraction were tested and compared. When applied to cDNA extracted from dissected brains of juvenile eels, the expression of TH was highest in the olfactory bulb, followed by the telencephalon including preoptic area, and the di-/mesencephalic areas excluding the optic lobes. TH expression in the optic lobes and in the medulla oblongata was low, whereas no expression could be detected in corpus cerebellum. This distribution pattern is in agreement with earlier studies on TH in the eel using immunohistochemistry, RT-PCR, and Northern blotting. The developed qrtRT-PCR assay provides a new tool for understanding the mechanisms regulating central DA inhibition of puberty in juvenile eels.

Algorithms↗

PubMed2005

Regulatory gene expressions in the ascidian ventral sensory vesicle: evolutionary relationships with the vertebrate hypothalamus.

In extant chordates, the overall patterning along the anteroposterior and dorsoventral axes of the neural tube is remarkably conserved. It has thus been proposed that four domains corresponding to the vertebrate presumptive forebrain, midbrain-hindbrain transition, hindbrain, and spinal cord were already present in the common chordate ancestor. To obtain insights on the evolution of the patterning of the anterior neural tube, we performed a study aimed at characterizing the expression of regulatory genes in the sensory vesicle of Ciona intestinalis, the anteriormost part of the central nervous system (CNS) related to the vertebrate forebrain, at tailbud stages. Selected genes encoded primarily for homologues of transcription factors involved in vertebrate forebrain patterning. Seven of these genes were expressed in the ventral sensory vesicle. A prominent feature of these ascidian genes is their restricted and complementary domains of expression at tailbud stages. These patterning markers thus refine the map of the developing sensory vesicle. Furthermore, they allow us to propose that a large part of the ventral and lateral sensory vesicle consists in a patterning domain corresponding to the vertebrate presumptive hypothalamus.

Animals↗

PubMed2005

The dopamine-synthesizing cells in the swimming larva of the tunicate Ciona intestinalis are located only in the hypothalamus-related domain of the sensory vesicle.

Dopamine is a major neuromodulator synthesized by numerous cell populations in the vertebrate forebrain and midbrain. Owing to the simple organization of its larval nervous system, ascidian tunicates provide a useful model to investigate the anatomy, neurogenesis and differentiation of the dopaminergic neural network underlying the stereotypical swimming behaviour of its chordate-type larva. This study provides a high-resolution cellular analysis of tyrosine hydroxylase (TH)-positive and dopamine-positive cells in Ciona intestinalis embryos and larvae. Dopamine cells are present only in the sensory vesicle of the Ciona larval brain, which may be an ancestral chordate feature. The dopamine-positive cells of the ascidian sensory vesicle are located in the expression domain of homologues of vertebrate hypothalamic markers. We show here that the larval coronet cells also arise from this domain. As a similar association between coronet cells and the hypothalamus was reported in bony and cartilaginous fishes, we propose that part of the ascidian ventral sensory vesicle is the remnant of a proto-hypothalamus that may have been present in the chordate ancestor. As dopaminergic cells are specified in the hypothalamus in all vertebrates, we suggest that the mechanisms of dopamine cell specification are conserved in the hypothalamus of Ciona and vertebrates. To test this hypothesis, we have identified new candidate regulators of dopaminergic specification in Ciona based on their expression patterns, which can now be compared with those in vertebrates.

Animals↗

PubMed2004

Preliminary observations on the spawning conditions of the European amphioxus (Branchiostoma lanceolatum) in captivity.

Members of the subphylum Cephalochordata, which include the genus Branchiostoma (i.e. amphioxus), represent the closest living invertebrate relatives of the vertebrates. To date, developmental studies have been carried out on three amphioxus species (the European Branchiostoma lanceolatum, the East Asian B. belcheri, and Floridian-Caribbean B. floridae). In most instances, adult animals have been collected from the field during their ripe season and allowed (or stimulated) to spawn in the laboratory. In any given year, dates of laboratory pawning have been limited by two factors. First, natural populations of these three most studied species of amphioxus are ripe, at most, for only a couple of months each year and, second, even when apparently ripe, animals spawn only at unpredictable intervals of every several days. This limited supply of living material hinders the development of amphioxus as a model system because this limitation makes it more difficult to work out protocols for new laboratory techniques. Therefore we are developing laboratory methods for increasing the number of amphioxus spawning dates per year. The present study found that a Mediterranean population of B. lanceolatum living near the Franco-Spanish border spawned naturally at the end of May and again at the end of June in 2003. Re-feeding experiments in the laboratory demonstrated that the gonads emptied at the end of May refilled with gametes by the end of June. We also found that animals with large gonads (both, obtained from the field and kept and fed at the laboratory during several weeks) could be induced to spawn in the laboratory out of phase with the field population if they were temperature shocked (spawning occurred 36 hours after a sustained increase in water temperature from 19 degrees C to 25 degrees C).

Animal Husbandry↗

PubMed2004

Dopamine inhibits luteinizing hormone synthesis and release in the juvenile European eel: a neuroendocrine lock for the onset of puberty.

In various adult teleost fishes, LH ovulatory peak is under a dual neurohormonal control that is stimulatory by GnRH and inhibitory by dopamine (DA). We investigated whether DA could also be involved in the inhibitory control of LH at earlier steps of gametogenesis by studying the model of the European eel, Anguilla anguilla, which remains at a prepubertal stage until the oceanic reproductive migration. According to a protocol previously developed in the striped bass, eels received sustained treatments with GnRH agonist (GnRHa), DA-receptor antagonist (pimozide), and testosterone (T) either alone or in combination. Only the triple treatment with T, GnRHa, and pimozide could trigger dramatic increases in LH synthesis and release as well as in plasma vitellogenin levels and a stimulation of ovarian vitellogenesis. Thus, in the prepubertal eel, removal of DA inhibition is required for triggering GnRH-stimulated LH synthesis and release as well as ovarian development. To locate the anatomical support for DA inhibition, the distribution of tyrosine hydroxylase (TH) in the brain and pituitary was studied by immunocytochemistry. Numerous TH-immunoreactive cell bodies were observed in the preoptic anteroventral nucleus, with a dense tract of immunoreactive fibers reaching the pituitary proximal pars distalis, where the gonadotrophs are located. This pathway corresponds to that mediating the inhibition of LH and ovulation in adult teleosts. To our knowledge, this is the first demonstration of a pivotal role for DA in the control of LH and puberty in a juvenile teleost. These data support the view that DA inhibition on LH secretion is an ancient evolutionary component in the neuroendocrine regulation of reproduction that may have been partially maintained throughout vertebrate evolution.

Animals↗

PubMed2004

The adult central nervous cholinergic system of a neurogenetic model animal, the zebrafish Danio rerio.

The central nervous cholinergic system of the zebrafish (Danio rerio), a model animal for neurogenetics, is documented here using immunohistochemical methods for visualizing choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme. Neuronal cell bodies containing ChAT are present in the telencephalon (lateral nucleus of ventral telencephalic area), preoptic region (anterior/posterior parvocellular and magnocellular preoptic nuclei), diencephalon (habenula, dorsal thalamus, posterior tuberculum), mesencephalon (Edinger-Westphal (EW) nucleus, oculomotor nerve nucleus, rostral tegmental nucleus, tectal type XIV neurons), isthmic region (nucleus lateralis valvulae, secondary gustatory-viscerosensory nucleus, nucleus isthmi (NI), perilemniscal nucleus, superior reticular nucleus (SRN)) and rhombencephalon (trochlear, trigeminal, abducens, facial, glossopharyngeal-vagal motor nerve nuclei, rostral and caudal populations of octavolateralis efferent neurons). In addition, some ChAT positive neurons are present in the rhombencephalic reticular formation, the central gray, and in cells accompanying the descending trigeminal tract. Obvious ChAT positive terminal fields are present in the supracommissural nucleus of area ventralis telencephali and the medial zone of area dorsalis telencephali, parvocellular superficial pretectal nucleus, torus semicircularis, medial octavolateralis nucleus, facial, glossopharyngeal, and vagal lobes, and in the inferior lobe (around the periventricular nucleus of the lateral recess and in the diffuse nucleus). The identification of all central nervous cholinergic systems provided here in this model system is pivotal for future detailed studies of their development and maintenance, e.g., with regard to the zebrafish ventral telencephalic and isthmic superior reticular neuronal populations, likely representing the homologues of at least part of the cholinergic basal forebrain and pedunculopontine/laterodorsal tegmental ascending activating systems of mammals, respectively.

Animals↗

PubMed2004

alpha-Synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson's disease.

Parkinson's disease (PD) is a slow progressive neurodegenerative disorder. Recent evidence suggests a central role for alpha-synuclein, a protein of unknown function, in the genesis of PD. The phenomenon of selective degeneration of dopaminergic neurons in PD may be linked to the potential toxicity of dopamine itself and aberrations in the processes which regulate dopamine content may underlie the pathogenesis of this disease. Here, we review a vital role of alpha-synuclein in the modulation of dopamine transporter (DAT) function, and describe how disruption of this modulatory process permits increased re-uptake of high levels of intracellular dopamine by DAT, causing profound neurotoxicity.

Animals↗

PubMed2004

Trypsin disrupts the trafficking of the human dopamine transporter by alpha-synuclein and its A30P mutant.

Alpha-synuclein modulates dopamine homeostasis in dopamine-producing neurons of substantia nigra, partly through regulation of human dopamine transporter (hDAT) activity. To identify the underlying mechanisms, we disrupted the modulation of hDAT activity by wild-type (wt) alpha-synuclein, and its familial Parkinson's disease linked mutants A30P and A53T, by mild trypsinization (0.1%, 30 s) of Ltk(-) cotransfected cells. Trypsin completely reversed the attenuation of hDAT function mediated by wt and the A30P mutant. In A53T coexpressing cells, where DAT activity is not downregulated, trypsinization did not induce any changes. These effects of trypsin were mimicked by collagenase I and Dispase (0.1%, 1 min each) but not by chymotrypsin, Pronase, or papain (0.1%, up to 2 min each). Trypsin increased dopamine uptake in rat primary mesencephalic neurons, suggesting that DAT activity is also subjected to modulation by alpha-synuclein in these neurons that endogenously coexpress both proteins. In trypsinized cells, dopamine accelerated both production of reactive oxygen species and cell death in hDAT and wt or A30P, but not A53T, coexpressing cells, compared to nontrypsinized cells. Paradoxically, trypsin increased the protein-protein interactions between the synuclein variants and hDAT, without any noticeable proteolysis of these proteins. hDAT-alpha-synuclein protein-protein interactions occurred through residues 58-107 (NAC domain) of the alpha-synuclein variants and residues 598-620 of the carboxy-terminal tail of hDAT, in both trypsinized and nontrypsinized cells. Confocal microscopy and biotinylation studies show that, in cells expressing the wt or A30P variants, but not the A53T mutant, hDAT is sequestered away from the plasma membrane into the cytoplasm, an effect that is reversed by trypsin. These results show that alpha-synuclein modulates hDAT function through trafficking of the transporter in a process that can be disrupted by trypsin.

Alanine↗

PubMed2004

Distribution of tyrosine hydroxylase, dopamine, and serotonin in the central nervous system of amphioxus (Branchiostoma lanceolatum): implications for the evolution of catecholamine systems in vertebrates.

To investigate the evolutionary transition that has shaped the catecholaminergic systems of vertebrates, the organization of catecholamine-synthesizing neurons and the nature of the catecholamines were examined in the central nervous system of adult amphioxus (Branchiostoma lanceolatum), a cephalochordate. We isolated a gene transcript encoding tyrosine hydroxylase (TH), the limiting enzyme of catecholamine biosynthesis, and studied its distribution together with that of dopamine and serotonin. Dopamine and TH are found in the same neurons of which they are three separate populations. Two are located in the anterior brain, the first being dorsal and lying in a row and the second being more posterior and lateral. A third population comprising a few dorsal commissural neurons was found in the posterior brain. The anterior dopaminergic cells innervate the ventral commissure of the cephalic vesicle, the hindbrain, and the spinal cord. A serotonin-containing cell group is located in the same plane as the second dopaminergic cell population but is more caudal, marking the probable transition between anterior brain and hindbrain, as deduced from gene expression patterns. The overall distribution of dopaminergic and serotoninergic systems is similar in amphioxus and vertebrate central nervous system and could be an ancestral character of chordates. As assayed by high-performance liquid chromatography and electrochemical detection, significant amounts of dopamine and octopamine, but not of noradrenaline, are present in amphioxus head. This finding is consistent with data obtained from most prostomian species. We conclude that the noradrenergic system is probably an innovation of vertebrates that appeared along with the neural crest and specific hindbrain nuclei.

Amino Acid Sequence↗

PubMed2004

Delineation of the conserved functional properties of D1A, D1B and D1C dopamine receptor subtypes in vertebrates.

The three main subtypes of dopamine D(1) receptor (D(1A), D(1B) and D(1C)) subtypes found in most vertebrate groups were generated by two major steps of gene duplications, early in evolution. To identify the functional characteristics contributing to conservation of these paralogous D(1) receptors in vertebrates, the pharmacological and functional properties of fish (Anguilla anguilla), amphibian (Xenopus laevis) and human receptors were systematically analysed in transfected cells. The ligand-binding parameters appeared essentially similar for orthologous receptors, but differed significantly among the subtypes. The D(1A) receptors from the three species displayed low intrinsic activity and a fast rate of agonist-induced desensitization. All the orthologous D(1B) receptors exhibited a similar desensitization time-course, but with smaller amplitude of decrease than D(1A) receptors, in agreement with their higher basal activity. In contrast, D(1C) receptors, which do not exist in mammals, have low intrinsic activity and exhibit only weak, but rapid, agonist-induced desensitization, without any changes upon longer treatment with agonist. Thus, each of the three D(1) receptor subtypes are characterized by activation and desensitization properties, in a sequence-specific manner, which has been probably acquired early after gene duplications, and constrained their conservation during vertebrate evolution. These properties have been instrumental to adapt dopamine system to the physiology of the numerous neuronal networks and functions they control in the large and complex brains of vertebrates.

Animals↗

PubMed2004

Cloning and developmental expression patterns of Dlx2, Lhx7 and Lhx9 in the medaka fish (Oryzias latipes).

We have isolated three homeodomain and LIM-homeodomain developmental transcription factors from the medaka fish (Oryzias latipes): OlDlx2, OlLhx7, and OlLhx9, and we have studied their expression patterns in the developing and adult brain. This analysis showed that OlDlx2 and OlLhx7 (together with OlNkx2.1b) delineate the subpallial divisions of the medaka telencephalon, and that OlLhx9 exhibits a typical and specific topology of expression in the pallium and diencephalic neuromeres. The expression patterns of these three genes, when compared in details with those of their tetrapod homologs, reveal both commonalities and differences in the basic organization of the developing teleost and vertebrate forebrain.

Amino Acid Sequence↗

PubMed2004

Does alpha-synuclein modulate dopaminergic synaptic content and tone at the synapse?

alpha-Synuclein is a key component of the pathological process of neurodegeneration in Parkinson's disease. Although its contributions to normal physiological conditions remain elusive, converging observations suggest that a primary function of this protein in dopaminergic neurons may be the regulation of dopamine content and synaptic tone at the synapse. We review here cumulative evidence that demonstrates the participation of alpha-synuclein in the life cycle of dopamine from its synthesis, storage, release, and reuptake. The regulatory role of alpha-synuclein on dopamine metabolism is assessed by discussing the experimental evidence supporting each of these observations in the healthy physiological maintenance of dopaminergic neurons, as well as showing how disruption of these events can initiate the observed neurotoxicity of alpha-synuclein and the genesis of the degenerative processes associated with Parkinson's disease.

Animals↗

PubMed2004

The degeneration of dopamine neurons in Parkinson's disease: insights from embryology and evolution of the mesostriatocortical system.

Parkinson's disease (PD) is, to a large extent, specific to the human species. Most symptoms are the consequence of the preferential degeneration of the dopamine-synthesizing cells of the mesostriatal-mesocortical neuronal pathway. Reasons for that can be traced back to the evolutionary mechanisms that shaped the dopamine neurons in humans. In vertebrates, dopamine-containing neurons and nuclei do not exhibit homogenous phenotypes. In this respect, mesencephalic dopamine neurons of the substantia nigra and ventral tegmental area are characterized by a molecular combination (tyrosine hydroxylase, aromatic amino acid decarboxylase, monoamine oxidase, vesicular monoamine transporter, dopamine transporter--to name a few), which is not found in other dopamine-containing neurons of the vertebrate brain. In addition, the size of these mesencephalic DA nuclei is tremendously expanded in humans as compared to other vertebrates. Differentiation of the mesencephalic neurons during development depends on genetic mechanisms, which also differ from those of other dopamine nuclei. In contrast, pathophysiological approaches to PD have highlighted the role of ubiquitously expressed molecules such as a-synuclein, parkin, and microtubule-associated proteins. We propose that the peculiar phenotype of the dopamine mesencephalic neurons, which has been selected during vertebrate evolution and reshaped in the human lineage, has also rendered these neurons particularly prone to oxidative stress, and thus, to the fairly specific neurodegeneration of PD. Numerous evidence has been accumulated to demonstrate that perturbed regulation of DAT-dependent dopamine uptake, DAT-dependent accumulation of toxins, dysregulation of TH activity as well as high sensitivity of DA mesencephalic neurons to oxidants are key components of the neurodegeneration process of PD. This view points to the contribution of nonspecific mechanisms (alpha-synuclein aggregation) in a highly specific cellular environment (the dopamine mesencephalic neurons) and provides a robust framework to develop novel and rational therapeutic schemes in PD.

Animals↗

PubMed2004

The role of alpha-synuclein in both neuroprotection and neurodegeneration.

Although alpha-synuclein is a central player in the pathophysiology of the dopaminergic neurodegeneration that occurs in Parkinson's disease (PD), emerging results suggest that the fundamental property of the wild-type form of this protein may be one of neuroprotection, as it can inhibit apoptosis in response to various pro-apoptotic stimuli. Such properties may be lost by its familial PD-linked mutations upon alterations in its expression levels or clearance (overexpression of the gene, reduced protein degradation) or following exposure to certain neurotoxins. Moreover, converging observations suggest that a primary function for alpha-synuclein in dopaminergic neurons may be the regulation of dopamine content and tone at the synapse. In this paper, we review how, indeed, alpha-synuclein regulates both the synthesis of dopamine, its storage into vesicles, its release in the synapse, and its re-uptake into the dopaminergic neurons. We also show how disruption of these events, and of the neuroprotective effects of alpha-synuclein, can initiate the observed neurotoxicity of alpha-synuclein in dopaminergic neurons and the genesis of the degenerative processes associated with PD.

Animals↗