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Mechanisms of alpha-synuclein action on neurotransmission: cell-autonomous and non-cell autonomous role.

Emanuele M, Chieregatti E - Biomolecules (2015)

Bottom Line: Mutations and duplication/triplication of the alpha-synuclein (αSyn)-coding gene have been found to cause familial Parkinson's disease (PD), while genetic polymorphisms in the region controlling the expression level and stability of αSyn have been identified as risk factors for idiopathic PD, pointing to the importance of wild-type (wt) αSyn dosage in the disease.Evidence that αSyn is present in the cerebrospinal fluid and interstitial brain tissue and that healthy neuronal grafts transplanted into PD patients often degenerate suggests that extracellularly-released αSyn plays a role in triggering the neurodegenerative process. αSyn's role in neurotransmission has been shown in various cell culture models in which the protein was upregulated or deleted and in knock out and transgenic animal, with different results on αSyn's effect on synaptic vesicle pool size and mobilization, αSyn being proposed as a negative or positive regulator of neurotransmitter release.In this review, we discuss the effect of αSyn on pre- and post-synaptic compartments in terms of synaptic vesicle trafficking, calcium entry and channel activity, and we focus on the process of exocytosis and internalization of αSyn and on the spreading of αSyn-driven effects due to the presence of the protein in the extracellular milieu.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy. marco.emanuele@iit.it.

ABSTRACT
Mutations and duplication/triplication of the alpha-synuclein (αSyn)-coding gene have been found to cause familial Parkinson's disease (PD), while genetic polymorphisms in the region controlling the expression level and stability of αSyn have been identified as risk factors for idiopathic PD, pointing to the importance of wild-type (wt) αSyn dosage in the disease. Evidence that αSyn is present in the cerebrospinal fluid and interstitial brain tissue and that healthy neuronal grafts transplanted into PD patients often degenerate suggests that extracellularly-released αSyn plays a role in triggering the neurodegenerative process. αSyn's role in neurotransmission has been shown in various cell culture models in which the protein was upregulated or deleted and in knock out and transgenic animal, with different results on αSyn's effect on synaptic vesicle pool size and mobilization, αSyn being proposed as a negative or positive regulator of neurotransmitter release. In this review, we discuss the effect of αSyn on pre- and post-synaptic compartments in terms of synaptic vesicle trafficking, calcium entry and channel activity, and we focus on the process of exocytosis and internalization of αSyn and on the spreading of αSyn-driven effects due to the presence of the protein in the extracellular milieu.

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Mechanisms of αSyn release and internalization. αSyn can be released from healthy neurons by conventional exocytosis of vesicles or MVB, or through exosomes, or can pass the membrane with the help of an unknown carrier. αSyn can enter neurons by internalization in vesicles, or through pores formed into the membrane by αSyn oligomers, or by direct translocation across the plasma membrane.
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biomolecules-05-00865-f002: Mechanisms of αSyn release and internalization. αSyn can be released from healthy neurons by conventional exocytosis of vesicles or MVB, or through exosomes, or can pass the membrane with the help of an unknown carrier. αSyn can enter neurons by internalization in vesicles, or through pores formed into the membrane by αSyn oligomers, or by direct translocation across the plasma membrane.

Mentions: The question of how extracellular αSyn in both the monomeric and oligomeric form contributes to neuronal toxicity in PD has been the subject of intensive research. Extracellular proteolytic enzymes, as matrix metalloproteases, were shown to degrade αSyn with the production of smaller protein species highly prone to aggregation [163]. Besides being extracellularly degraded, αSyn might be internalized by neurons [164], microglia [165,166] and astrocytes [167]. Many studies focused on the mechanism of αSyn uptake into cells. One hypothesis suggests the ability of αSyn oligomers to form pentameric pore-like structures in cell membranes that increase intracellular calcium, leading to oxidative stress, lysosomal leakage and mitochondrial dysfunction, resulting in cell vulnerability and neurodegeneration [168]. Feng et al. used a dopaminergic-like cell model with regulated αSyn expression, reporting an increase in membrane permeability and conductance due to pore formation. More importantly, they show for the first time that the extracellular application of an anti-αSyn antibody reverts the effects on membrane permeability, suggesting an αSyn interaction with the outer surface of the cell membrane [126]. Danzer et al. entered more in detail about αSyn species and showed that different aggregation conditions produce heterogeneous populations of αSyn oligomers, which can be differentiated on the basis of their biophysical properties and cellular effects. SH-SY5Y cells treated with Type A oligomers induced an increased membrane permeability and triggered cell death, while Type B and C oligomers were able to enter cells directly and to seed intracellular αSyn aggregation [125]. Moreover, they demonstrated that the Type C oligomers are capable of inducing transmembrane αSyn seeding in a dose- and time-dependent manner, also in cortical primary neurons [169]. Lee et al. showed that the internalization of αSyn aggregates in cells is inhibited by the expression of a dominant-negative dynamin-1 or by low temperature, indicating that the internalization depends on endocytosis. More in depth, they demonstrated that this form of endocytosis of αSyn aggregates depends on an unknown membrane surface receptor [170]. Many authors suggest that monomeric αSyn internalization occurs very rapidly via a mechanism distinct from normal endocytosis. In fact, they show that the protein is detectable in the cytoplasm of the cells after five minutes of incubation. Moreover, the import of αSyn is not affected by temperature or the inhibitor of endocytosis, suggesting a direct translocation across the plasma membrane [167,170]. These distinctions were partially contradicted by the very recent finding that neuron-to-neuron transfer of monomeric, oligomeric, as well as fibrillar αSyn relied on endocytic processes, as demonstrated by experiments performed with selective endocytosis inhibitors, both in vitro and in vivo [171]. Sung et al. suggest that αSyn alone is not able to traverse the membrane and identified a possible carrier with a 60-kDa molecular size, which appears to bind to αSyn in a specific way [164]. Membrane trafficking plays a central role in the maintenance of cell organization and organelle homeostasis and is necessary for intercellular signaling [172]. Chai et al. in their work used transferrin-mediated iron uptake [173] to study alteration in intracellular trafficking induced by αSyn oligomers. They show that after internalization of the oligomers, the rate of transferrin receptor recycling is increased, and consequently, the surface expression of the receptor is modified. [174]. It has been suggested that microglial inflammation augments the progression of PD [175]. Using different primary mesencephalic cultures, Zhang et al. demonstrated that αSyn aggregates can be phagocytized into microglia cells. Subsequent activation of NADPH oxidase plays a central role in microglial activation of the inflammation process, leading to neurotoxicity [165]. Similar results were obtained by performing experiments with primary astrocytic cultures or astrocytoma cell lines, which exhibited the acquisition of a reactive phenotype upon incubation with extracellular αSyn [176,177]. The toxic phenotype observed in neurons seems to derive from the non-cell autonomous interaction between neurons and glia, mediated by αSyn, which may lead to chronic inflammation. It has to be reminded that both PD-affected patients and animal models show signs of chronic inflammation. Since αSyn seems to be implicated in exocytosis [20] and in the recycling of the synaptic vesicles [21], accumulation of αSyn monomers as a result of constant internalization could also alter the physiological state of membrane trafficking and synaptic transmission. The model in Figure 2 depicts various possible routes of release and internalization of αSyn.


Mechanisms of alpha-synuclein action on neurotransmission: cell-autonomous and non-cell autonomous role.

Emanuele M, Chieregatti E - Biomolecules (2015)

Mechanisms of αSyn release and internalization. αSyn can be released from healthy neurons by conventional exocytosis of vesicles or MVB, or through exosomes, or can pass the membrane with the help of an unknown carrier. αSyn can enter neurons by internalization in vesicles, or through pores formed into the membrane by αSyn oligomers, or by direct translocation across the plasma membrane.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496700&req=5

biomolecules-05-00865-f002: Mechanisms of αSyn release and internalization. αSyn can be released from healthy neurons by conventional exocytosis of vesicles or MVB, or through exosomes, or can pass the membrane with the help of an unknown carrier. αSyn can enter neurons by internalization in vesicles, or through pores formed into the membrane by αSyn oligomers, or by direct translocation across the plasma membrane.
Mentions: The question of how extracellular αSyn in both the monomeric and oligomeric form contributes to neuronal toxicity in PD has been the subject of intensive research. Extracellular proteolytic enzymes, as matrix metalloproteases, were shown to degrade αSyn with the production of smaller protein species highly prone to aggregation [163]. Besides being extracellularly degraded, αSyn might be internalized by neurons [164], microglia [165,166] and astrocytes [167]. Many studies focused on the mechanism of αSyn uptake into cells. One hypothesis suggests the ability of αSyn oligomers to form pentameric pore-like structures in cell membranes that increase intracellular calcium, leading to oxidative stress, lysosomal leakage and mitochondrial dysfunction, resulting in cell vulnerability and neurodegeneration [168]. Feng et al. used a dopaminergic-like cell model with regulated αSyn expression, reporting an increase in membrane permeability and conductance due to pore formation. More importantly, they show for the first time that the extracellular application of an anti-αSyn antibody reverts the effects on membrane permeability, suggesting an αSyn interaction with the outer surface of the cell membrane [126]. Danzer et al. entered more in detail about αSyn species and showed that different aggregation conditions produce heterogeneous populations of αSyn oligomers, which can be differentiated on the basis of their biophysical properties and cellular effects. SH-SY5Y cells treated with Type A oligomers induced an increased membrane permeability and triggered cell death, while Type B and C oligomers were able to enter cells directly and to seed intracellular αSyn aggregation [125]. Moreover, they demonstrated that the Type C oligomers are capable of inducing transmembrane αSyn seeding in a dose- and time-dependent manner, also in cortical primary neurons [169]. Lee et al. showed that the internalization of αSyn aggregates in cells is inhibited by the expression of a dominant-negative dynamin-1 or by low temperature, indicating that the internalization depends on endocytosis. More in depth, they demonstrated that this form of endocytosis of αSyn aggregates depends on an unknown membrane surface receptor [170]. Many authors suggest that monomeric αSyn internalization occurs very rapidly via a mechanism distinct from normal endocytosis. In fact, they show that the protein is detectable in the cytoplasm of the cells after five minutes of incubation. Moreover, the import of αSyn is not affected by temperature or the inhibitor of endocytosis, suggesting a direct translocation across the plasma membrane [167,170]. These distinctions were partially contradicted by the very recent finding that neuron-to-neuron transfer of monomeric, oligomeric, as well as fibrillar αSyn relied on endocytic processes, as demonstrated by experiments performed with selective endocytosis inhibitors, both in vitro and in vivo [171]. Sung et al. suggest that αSyn alone is not able to traverse the membrane and identified a possible carrier with a 60-kDa molecular size, which appears to bind to αSyn in a specific way [164]. Membrane trafficking plays a central role in the maintenance of cell organization and organelle homeostasis and is necessary for intercellular signaling [172]. Chai et al. in their work used transferrin-mediated iron uptake [173] to study alteration in intracellular trafficking induced by αSyn oligomers. They show that after internalization of the oligomers, the rate of transferrin receptor recycling is increased, and consequently, the surface expression of the receptor is modified. [174]. It has been suggested that microglial inflammation augments the progression of PD [175]. Using different primary mesencephalic cultures, Zhang et al. demonstrated that αSyn aggregates can be phagocytized into microglia cells. Subsequent activation of NADPH oxidase plays a central role in microglial activation of the inflammation process, leading to neurotoxicity [165]. Similar results were obtained by performing experiments with primary astrocytic cultures or astrocytoma cell lines, which exhibited the acquisition of a reactive phenotype upon incubation with extracellular αSyn [176,177]. The toxic phenotype observed in neurons seems to derive from the non-cell autonomous interaction between neurons and glia, mediated by αSyn, which may lead to chronic inflammation. It has to be reminded that both PD-affected patients and animal models show signs of chronic inflammation. Since αSyn seems to be implicated in exocytosis [20] and in the recycling of the synaptic vesicles [21], accumulation of αSyn monomers as a result of constant internalization could also alter the physiological state of membrane trafficking and synaptic transmission. The model in Figure 2 depicts various possible routes of release and internalization of αSyn.

Bottom Line: Mutations and duplication/triplication of the alpha-synuclein (αSyn)-coding gene have been found to cause familial Parkinson's disease (PD), while genetic polymorphisms in the region controlling the expression level and stability of αSyn have been identified as risk factors for idiopathic PD, pointing to the importance of wild-type (wt) αSyn dosage in the disease.Evidence that αSyn is present in the cerebrospinal fluid and interstitial brain tissue and that healthy neuronal grafts transplanted into PD patients often degenerate suggests that extracellularly-released αSyn plays a role in triggering the neurodegenerative process. αSyn's role in neurotransmission has been shown in various cell culture models in which the protein was upregulated or deleted and in knock out and transgenic animal, with different results on αSyn's effect on synaptic vesicle pool size and mobilization, αSyn being proposed as a negative or positive regulator of neurotransmitter release.In this review, we discuss the effect of αSyn on pre- and post-synaptic compartments in terms of synaptic vesicle trafficking, calcium entry and channel activity, and we focus on the process of exocytosis and internalization of αSyn and on the spreading of αSyn-driven effects due to the presence of the protein in the extracellular milieu.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy. marco.emanuele@iit.it.

ABSTRACT
Mutations and duplication/triplication of the alpha-synuclein (αSyn)-coding gene have been found to cause familial Parkinson's disease (PD), while genetic polymorphisms in the region controlling the expression level and stability of αSyn have been identified as risk factors for idiopathic PD, pointing to the importance of wild-type (wt) αSyn dosage in the disease. Evidence that αSyn is present in the cerebrospinal fluid and interstitial brain tissue and that healthy neuronal grafts transplanted into PD patients often degenerate suggests that extracellularly-released αSyn plays a role in triggering the neurodegenerative process. αSyn's role in neurotransmission has been shown in various cell culture models in which the protein was upregulated or deleted and in knock out and transgenic animal, with different results on αSyn's effect on synaptic vesicle pool size and mobilization, αSyn being proposed as a negative or positive regulator of neurotransmitter release. In this review, we discuss the effect of αSyn on pre- and post-synaptic compartments in terms of synaptic vesicle trafficking, calcium entry and channel activity, and we focus on the process of exocytosis and internalization of αSyn and on the spreading of αSyn-driven effects due to the presence of the protein in the extracellular milieu.

Show MeSH
Related in: MedlinePlus