α-Synuclein-mediated inhibition of ATF6 processing into COPII vesicles disrupts UPR signaling in Parkinson's disease.

The unfolded protein response (UPR) monitors the folding environment within the endoplasmic reticulum (ER). Accumulation of misfolded proteins within the ER activates the UPR resulting in the execution of adaptive or non-adaptive signaling pathways. α-Synuclein (α-syn) whose accumulation and aggregation define the pathobiology of Parkinson's disease (PD) has been shown to inhibit ER-Golgi transit of COPII vesicles. ATF6, a protective branch of the UPR, is processed via COPII mediated ER-Golgi transit following its activation via ER stress. Using cellular PD models together with biochemical reconstitution assays, we showed that α-syn inhibited processing of ATF6 directly through physical interactions and indirectly through restricted incorporation into COPII vesicles. Impaired ATF6 signaling was accompanied by decreased ER-associated degradation (ERAD) function and increased pro-apoptotic signaling. The mechanism by which α-syn inhibits ATF6 signaling expands our understanding of the role ER stress and the UPR play in neurodegenerative diseases such as PD.

Hyperphosphorylated Tau in an α-synuclein-overexpressing transgenic model of Parkinson's disease.

Although clinically distinct diseases, tauopathies and synucleinopathies share a common genesis and mechanisms, leading to overlapping degenerative changes within neurons. In human postmortem striatum of Parkinson's disease (PD) and PD with dementia, we have recently described elevated levels of tauopathy, indexed as increased hyperphosphorylated Tau (p-Tau). Here we assessed tauopathy in striatum of a transgenic animal model of PD, overexpressing human α-synuclein under the platelet-derived growth factor promoter. At 11 months of age, large and progressive increases in p-Tau in transgenic mice, hyperphosphorylated at sites reminiscent of Alzheimer's disease, were noted, along with elevated levels of α-synuclein and glycogen synthase kinase 3ß phosphorylated at Tyr216 (p-GSK-3ß), a major kinase involved in the hyperphosphorylation of Tau. Differential Triton X-100 extraction of striata showed the presence of aggregated α-synuclein in the transgenic mice, along with p-Tau and p-GSK-3ß, which was also confirmed through immunohistochemistry. After p-Tau formation, both Tau and microtubule-associated protein 1 (MAP1) dissociated from the cytoskeleton, consistent with the diminished ability of these cytoskeleton-binding proteins to bind microtubules. Increases in free tubulin and actin were also noted, indicative of cytoskeleton remodeling and destabilization. In vivo magnetic resonance imaging of the transgenic animals showed a reduction in brain volume of transgenic mice, indicating substantial atrophy. From immunohistochemical studies, α-synuclein, p-Tau and p-GSK-3ß were found to be overexpressed and co-localized in large inclusion bodies, reminiscent of Lewy bodies. The elevated state of tauopathy seen in these platelet-derived growth factor-α-synuclein mice provides further confirmation that PD may be a tauopathic disease.

Region-specific tauopathy and synucleinopathy in brain of the alpha-synuclein overexpressing mouse model of Parkinson's disease.

BACKGROUND: α-synuclein [α-Syn]-mediated activation of GSK-3ß leading to increases in hyperphosphorylated Tau has been shown by us to occur in striata of Parkinson's diseased [PD] patients and in animal models of PD. In Alzheimer's disease, tauopathy exists in several brain regions; however, the pattern of distribution of tauopathy in other brain regions of PD or in animal models of PD is not known. The current studies were undertaken to analyze the distribution of tauopathy in different brain regions in a widely used mouse model of PD, the α-Syn overexpressing mouse. RESULTS: High levels of α-Syn levels were seen in the brain stem, with a much smaller increase in the frontal cortex; neither cerebellum nor hippocampus showed any overexpression of α-Syn. Elevated levels of p-Tau, hyperphosphorylated at Ser202, Ser262 and Ser396/404, were seen in brain stem, with lower levels seen in hippocampus. In both frontal cortex and cerebellum, increases were seen only in p-Ser396/404 Tau, but not in p-Ser202 and p-Ser262. p-GSK-3ß levels were not elevated in any of the brain regions, although total GSK-3ß was elevated in brain stem. p-p38MAPK levels were unchanged in all brain regions examined, while p-ERK levels were elevated in brain stem, hippocampus and cerebellum, but not the frontal cortex. p-JNK levels were increased in brain stem and cerebellum but not in the frontal cortex or hippocampus. Elevated levels of free tubulin, indicating microtubule destabilization, were seen only in the brain stem. CONCLUSION: Our combined data suggest that in this animal model of PD, tauopathy, along with microtubule destabilization, exists primarily in the brain stem and striatum, which are also the two major brain regions known to express high levels of α-Syn and undergo the highest levels of degeneration in human PD. Thus, tauopathy in PD may have a very restricted pattern of distribution.

Mice expressing the A53T mutant form of human alpha-synuclein exhibit hyperactivity and reduced anxiety-like behavior.

Genetic mutations associated with alpha-synuclein (alpha-Syn) are implicated in the pathogenesis of Parkinson's disease (PD). PD is primarily a movement disorder, but patients are known to experience anxiety and other mood disorders. In this study, we examined the effect of the hA53T mutation during development by analyzing the protein expression of norepinephrine (NET), serotonin (SERT), and dopamine (DAT) transporters in addition to assessing locomotor and anxiety-like behavior. We observed significant decreases in DAT expression at 8 months in transgenic animals compared with normal and younger mice. We used the elevated plus maze, open-field test, and rotarod apparatus to evaluate wild-type and hA53T hemizygous mice at 2, 8, and 12 months of age. Our results showed that 12-month-old transgenic mice spend more time in the open arms and display a greater number of open entries of the elevated plus maze compared with wild-type controls and younger mice. Open-field test results showed that 12-month-old mice travel a greater distance overall and travel more in the inner zone than either wild-type or younger mice. Rotarod testing showed that 8- and 12-month-old transgenic mice perform better than either wild-type controls or younger mice. Overall, 8-12-month-old transgenic mice showed a trend toward reduced anxiety-like behavior and increased hyperactivity. These results indicate a possible role of the A53T alpha-Syn mutation in anxiety-like and hyperactive behaviors in a PD mouse model, suggesting that these behaviors might be comorbid with this disease.

Alpha-Synuclein contributes to GSK-3beta-catalyzed Tau phosphorylation in Parkinson's disease models.

We have shown in the parkinsonism-inducing neurotoxin MPP(+)/MPTP model that alpha-Synuclein (alpha-Syn), a presynaptic protein causal in Parkinson's disease (PD), contributes to hyperphosphorylation of Tau (p-Tau), a protein normally linked to tauopathies, such as Alzheimer's disease (AD). Here, we investigated the kinase involved and show that the Tau-specific kinase, glycogen synthase kinase 3beta (GSK-3beta), is robustly activated in various MPP(+)/MPTP models of Parkinsonism (SH-SY5Y cotransfected cells, mesencephalic neurons, transgenic mice overexpressing alpha-Syn, and postmortem striatum of PD patients). The activation of GSK-3beta was absolutely dependent on the presence of alpha-Syn, as indexed by the absence of p-GSK-3beta in cells lacking alpha-Syn and in alpha-Syn KO mice. MPP(+) treatment induced translocation and accumulation of p-GSK-3beta in nuclei of SH-SY5Y cells and mesencephalic neurons. Through coimmunoprecipitation (co-IP), we found that alpha-Syn, pSer396/404-Tau, and p-GSK-3beta exist as a heterotrimeric complex in SH-SY5Y cells. GSK-3beta inhibitors (lithium and TDZD-8) protected against MPP(+)-induced events in SH-SY5Y cells, preventing cell death and p-GSK-3beta formation, by reversing increases in alpha-Syn accumulation and p-Tau formation. These data unveil a previously unappreciated role of alpha-Syn in the induction of p-GSK-3beta, and demonstrate the importance of this kinase in the genesis and maintenance of neurodegenerative changes associated with PD.

Dopamine promotes striatal neuronal apoptotic death via ERK signaling cascades.

Although the mechanisms underlying striatal neurodegeneration are poorly understood, we have shown that striatal pathogenesis may be initiated by high synaptic levels of extracellular dopamine (DA). Here we investigated in rat striatal primary neurons the mobilization of the mitogen-activated protein kinase (MAPK) signaling pathways after treatment with DA. Instead of observing an elevation of the archetypical pro-cytotoxic MAPKs, p-JNK and p-p38 MAPK, we found that DA, acting through D1 DA receptors, induced a sustained stimulation of the phosphorylated form of extracellular signal-regulated kinase (p-ERK) via a cAMP/protein kinase A (PKA)/Rap1/B-Raf / MAPK/ERK kinase (MEK) pathway. Blockade of D2 DA receptors, beta-adrenergic receptors or N-methyl-D-aspartate receptors with receptor-specific antagonists had no significant effect on this process. Activation of D1 DA receptors and PKA by DA caused phosphorylation and inactivation of the striatal-enriched tyrosine phosphatase, an important phosphatase for the dephosphorylation and subsequent inactivation of p-ERK in the striatum. Interestingly, p-ERK was primarily retained in the cytoplasm, with only low amounts translocated to the nucleus. The scaffold protein beta-arrestin2 interacted with both p-ERK and D1 DA receptor, triggering the cytosolic retention of p-ERK and inducing striatal neuronal apoptotic death. These data provide unique insight into a novel role of p-ERK in striatal neurodegeneration.

Regulated interactions of the norepineprhine transporter by the actin and microtubule cytoskeletons.

One role of the actin cytoskeleton is to maintain the structural morphology and activity of the pre-synaptic terminal. We sought to determine if the actin cytoskeleton plays a role in regulating interactions between the norepinephrine transporter (NET) and alpha-Synuclein (alpha-Syn), two proteins expressed in the pre-synaptic terminal. In cells transfected with either 0.5 microg/mL or 3 microg/mL of alpha-Syn and 1 microg/mL of NET DNA, treatment with cytochalasin D, an actin depolymerizing agent, caused a dose-dependent decrease and increase, respectively, in [3H]-NE uptake. Protein interactions between NET, beta-actin, and alpha-Syn were modified, along with levels of surface transporters. Treatment of primary brainstem neurons and frontal cortex synaptosomes with cytochalasin D caused a 115% and 28% increase, respectively, in NET activity. Depolymerization of both actin and microtubules did not alter NET activity in cells with 0.5 microg/mL alpha-Syn, but caused an increase in [3H]-NE uptake in cells transfected with 3 microg/mL of alpha-Syn and primary neurons. This is the first direct demonstration of NET activity being regulated via actin and modulated by interactions with alpha-Syn.

Dopamine differentially induces aggregation of A53T mutant and wild type alpha-synuclein: insights into the protein chemistry of Parkinson's disease.

Aggregation of alpha-synuclein is known to be a causal factor in the genesis of Parkinson's disease and Dementia with Lewy bodies. Duplication and/or triplication and mutation of the alpha-synuclein gene are associated with sporadic and familial Parkinson's disease. Synucleinopathies appear to primarily affect dopaminergic neurons. The present studies investigate the role of dopamine in alpha-synuclein aggregation through NMR. Dopamine causes aggregation of both wild type and A53T mutant alpha-synuclein in a temperature-dependent manner, but the mutant A53T shows a greater propensity to aggregate in the presence of dopamine only at 37 degrees C. A single point mutation in the alpha-synuclein A53T mutant gene results in a structural change in the protein and drastically increases its propensity to aggregate in the presence of dopamine. The present data indicate that mutation in the alpha-synuclein gene may predispose the protein to dopamine-induced aggregation, thereby contributing to disease pathogenesis.

Alpha-synuclein induces hyperphosphorylation of Tau in the MPTP model of parkinsonism.

Many neurodegenerative diseases associated with functional Tau dysregulation, including Alzheimer's disease (AD) and other tauopathies, also show alpha-synuclein (alpha-Syn) pathology, a protein associated with Parkinson's disease (PD) pathology. Here we show that treatment of primary mesencephalic neurons (48 h) or subchronic treatment of wild-type (WT) mice with the Parkinsonism-inducing neurotoxin MPP+/MPTP, results in selective dose-dependent hyperphosphorylation of Tau at Ser396/404 (PHF-1-reactive Tau, p-Tau), with no changes in pSer202 but with nonspecific increases in pSer262 levels. The presence of alpha-Syn was absolutely mandatory to observe MPP+/MPTP-induced increases in p-Tau levels, since no alterations in p-Tau were seen in transfected cells not expressing alpha-Syn or in alpha-Syn-/- mice. MPP+/MPTP also induced a significant accumulation of alpha-Syn in both mesencephalic neurons and in WT mice striatum. MPTP/MPP+ lead to differential alterations in p-Tau and alpha-Syn levels in a cytoskeleton-bound, vs. a soluble, cytoskeleton-free fraction, inducing their coimmunoprecipitation in the cytoskeleton-free fraction and neuronal soma. Subchronic MPTP exposure increased sarkosyl-insoluble p-Tau in striatum of WT but not alpha-Syn-/- mice. These studies describe a novel mechanism for MPTP neurotoxicity, namely a MPTP-inducible, strictly alpha-Syn-dependent, increased formation of PHF-1-reactive Tau, suggesting convergent overlapping pathways in the genesis of clinically divergent diseases such as AD and PD.

An inflammatory pathomechanism for Parkinson's disease?

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc), striatal dopamine deficiency and appearance of Lewy bodies. Inflammatory and immune, or even autoimmune, stigmata, have been described in post-mortem brains of PD patients. Although disputed in humans, a reactive astrocytosis and a lymphocytic infiltration in the SNpc have been observed in animal models of PD, which need further examination. This review summarizes the current knowledge on brain inflammation in humans with PD, and how inflammation and/or (auto)immune reactions within the SNpc could be linked to other pathophysiological mechanisms that have been hypothesized for the etiology of PD, such as oxidative stress, exposure to neurotoxins, and post-infectious or post-traumatic injuries. In particular, we discuss how microglial cells could be activated during the course of PD, and present a new hypothesis that PD-linked protein (alpha-synuclein, in particular) aggregates could be implicated in their activation, to induce a chronic and sustained inflammation involved in the progression, at least, of the disease. The current status of anti-inflammatory agents, either already tried in PD clinical trials or putatively usefull as adjuvant therapies for PD, is also discussed.

Dopamine D1 receptor-mediated toxicity in human SK-N-MC neuroblastoma cells.

Striatal degeneration occurs through unknown mechanisms in certain neurodegenerative disorders characterized by increased and sustained synaptic levels of dopamine. In the present studies, we examined the effects of treatment of SK-N-MC neuroblastoma cells with dopamine to understand the participation of dopamine D(1) receptor in postsynaptic cytotoxicity. Treatment of SK-N-MC cells either with dopamine or the D(1) receptor agonist SKF R-38393 resulted in a significant increase in the production of reactive oxygen species (by approximately 2.75-fold) and cell death ( approximately 50%), while antagonism of the D(1) receptor with SCH 23390 significantly reversed (to approximately 75% of control level) these effects. Accumulation of cAMP in dopamine treated cells (t(1/2)=1.5h) preceded changes in ionic gradient (t(1/2)=6.5h), as measured by intracellular potassium concentration and leakage of cytochrome c into the cytosol (t(1/2)=13 h), suggesting a possible staging of toxic events as a result of activation of D(1) receptor by dopamine. Examination of cellular metabolic properties with (13)C NMR spectroscopy showed an inhibitory effect on tricarboxylic acid cycle metabolism via D(1)-mediated receptors after treatment with dopamine, suggesting a direct role for D(1) receptor in dopamine-induced postsynaptic cell death. The present studies provide novel insight into a possible patho-physiological staging of cytotoxic events that are mediated by activation of D(1) receptor.

The neurotoxin, MPP+, induces hyperphosphorylation of Tau, in the presence of alpha-Synuclein, in SH-SY5Y neuroblastoma cells.

Alzheimer's disease (AD) is characterized, in part, by intracellular neurofibrillary tangles composed of hyperphosphorylated filamentous aggregates of the microtubule-associated protein, Tau. Such hyperphosphorylated Tau is also found in Lewy bodies (LBs), and cytoplasmic inclusion bodies in certain forms of Parkinson's disease (PD). Further, LBs also contain aggregates of alpha-synuclein (alpha-Syn), also a microtubule-associated protein, which has been linked to the genesis of PD. To investigate a specific correlation between Tau phosphorylation and alpha-Syn, we generated a SH-SY5Y cell line that stably expresses human wild type alpha-Syn. Protein expression levels in the stably transfected cell line (SHalpha-Syn) were within the physiological range of alpha-Syn expression found in Substantia nigra. We show here, in the MPP+ (1-methyl-4-phenylpyridinium ion) cell model of parkinsonism, a time- and dose-dependent increase in the hyperphosphorylation of Tau at pSer396/404 (PHF-1-reactive Tau, p-Tau), concomitant with increased accumulation of alpha-Syn, upon treatment of cells with the neurotoxin. This increase in p-Tau was strictly dependent on the presence of alphaSyn, since in transfected cells not expressing any alpha-Syn, MPP+ failed to induce an increase in PHF-1-reactive Tau. The production of p-Tau caused increased cytotoxicity as indexed by reduced cell viability. Moreover, in the absence of alpha-Syn, the cells were more resistant to MPP+ -induced cell death. The increased levels of both p-Tau and alpha-Syn led to diminished levels of these proteins associated with the cytoskeleton, which was accompanied by enhanced presence of the proteins in the cytoskeletal-free fractions. These data indicate that alpha-Syn and p-Tau modulate the pathogenicity of one another, suggesting a novel convergent mechanism of neurodegeneration.

ER stress and Parkinson's disease: Pathological inputs that converge into the secretory pathway.

The major clinical feature of Parkinson's disease (PD) is impairment in motor control as a result of extensive dopaminergic neuron loss in the substantia nigra pars compacta. The central pathological hallmark of PD is the formation of neuronal cytoplasmic inclusions of insoluble proteins called Lewy bodies, of which fibrillar aggregates of misfolded αSynuclein are the major components. Despite intense research on the pathogenic mechanism that trigger neuronal loss and disease progression, the neurogenesis of PD remains unknown. However, studies on genetics of PD have identified specific genes and proteins linked to this disease. Genetic mutations linked with different forms of familial PD have unveiled a closer relationship between pathology and impairments at different points in the secretory pathway. Accumulation of misfolded/unfolded proteins in the endoplasmic reticulum and disruptions in protein clearance mechanisms result in activation of an adaptive stress pathway known as the unfolded protein response (UPR). UPR signaling is mediated by three stress sensors that induce independent and convergent signaling branches that help to maintain homeostasis, or eventually trigger cell death under chronic stress conditions. Signs of ER stress are observed in post-mortem tissue from sporadic human PD cases and in most animal models of the disease, implicating all three branches of this cellular response. However, the exact contribution of the UPR in the progression of PD or in dopaminergic neuron survival is not yet well understood. A large number of studies reveal a clear activation of the UPR in toxicological models resembling sporadic PD, where ATF6, XBP1 and CHOP have a functional role in controlling dopaminergic neuron survival in neurotoxin-based models of PD in vivo. Also pharmacological and gene therapy approaches aimed to target different points of this pathway have revealed an important functional role in PD pathogenesis. This article is part of a Special Issue entitled SI:ER stress.

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.

Modulation of dopamine transporter function by alpha-synuclein is altered by impairment of cell adhesion and by induction of oxidative stress.

Human alpha-synuclein accumulates in dopaminergic neurons as intraneuronal inclusions, Lewy bodies, which are characteristic of idiopathic Parkinson's disease (PD). Here, we suggest that modulation of the functional activity of the dopamine transporter (DAT) by alpha-synuclein may be a key factor in the preferential degeneration of mesencephalic dopamine (DA)-synthesizing neurons in PD. In cotransfected Ltk-, HEK 293, and SK-N-MC cells, alpha-synuclein induced a 35% decrease in [3H]DA uptake. Biotinylated DAT levels were decreased by 40% in cotransfected cells relative to cells expressing only DAT. DAT was colocalized with alpha-synuclein in mesencephalic neurons and cotransfected Ltk- cells. Coimmunoprecipitation studies showed the existence of a complex between alpha-synuclein and DAT, in specific rat brain regions and cotransfected cells, through specific amino acid motifs of both proteins. The attenuation of DAT function by alpha-synuclein was cytoprotective, because DA-mediated oxidative stress and cell death were reduced in cotransfected cells. The neurotoxin MPP+ (1-methyl-4-phenylpyridinium), oxidative stress, or impairment of cell adhesion ablated the alpha-synuclein-mediated inhibition of DAT activity, which caused increased uptake of DA and increased biotinylated DAT levels, in both mesencephalic neurons and cotransfected cells. These studies suggest a novel normative role for alpha-synuclein in regulating DA synaptic availability and homeostasis, which is relevant to the pathophysiology of PD.

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.

Differential expression of D2-like dopamine receptors in the kidney of the spontaneously hypertensive rat.

OBJECTIVE: To compare the expression and cellular distribution of D(2)-like dopamine receptors in the kidney of the spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto (WKY) rat. DESIGN: Renal D(2)-like receptor protein expression and distribution has not been studied in the SHR. Since changes in D(2)-like receptor expression and/or distribution may contribute to the dysregulation of renal dopamine and D(1A) receptor function, we examined the expression of the three subtypes of D(2)-like receptors (D(2), D(3) and D(4)) in SHR and WKY rat kidneys. METHODS: Western blot analysis and confocal immunocytochemistry with specific polyclonal antipeptide antibodies directed against the receptor subtypes, were used to assess protein expression. RESULTS: There were no differences in protein expression and cellular immunolocalization of the D(2) receptor subtypes between SHR and WKY rats. Expression of the 50 kDa D(3) receptor was reduced in the cortex of the SHR; no differences in D(3) receptor levels were seen in the inner medulla of SHR and WKY rats. The D(4) receptor polypeptides were overexpressed in the cortex of SHR, while in the inner medulla no difference in expression of the D(4) receptor proteins was observed between SHR and WKY rats. Immunocytochemistry also showed increased immunostaining of D(4) receptors in tubular structures in the cortex, but diminished staining in the SHR inner medulla. CONCLUSION: The observed differences in expression and distribution of D(3) and D(4) dopamine receptors between cortex and inner medulla of the kidneys of SHR and WKY rats may contribute to the aberrant state of dopaminergic-mediated natriuresis in SHR.

Inflammation and Parkinson's disease.

Numerous recent findings indicate the possible involvement of an immune mechanism in the pathogenesis of neurodegeneration. The immune reaction could either act as a primary event, generating changes leading to cell death, or could be a secondary response to neuronal injury. In various neurodegenerative disorders such as Alzheimer's, Huntington's or Pick's disease, Down's syndrome, multiple sclerosis and the AIDS-dementia complex, the inflammatory pathomechanism is strongly supported by experimental and clinical studies. Such inflammatory mechanisms have also been postulated in Parkinson's disease (PD). This review summarizes some generalities about inflammation and immune reactions in the context of the brain, and provides clinical, epidemiological and experimental data showing that inflammation and immunity, or even auto-immunity, could be implicated in PD, either in its initial step or in its progression. Different experimental models useful for studying the role(s) of inflammation and (auto)immunity in the neurodegenerative process of the dopaminergic neurons in PD are examined. The major similarities and differences between PD and other neurodegenerative disorders are discussed.

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.

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.