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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 (╬▒Syn)-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 ╬▒Syn have been identified as risk factors for idiopathic PD, pointing to the importance of wild-type (wt) ╬▒Syn dosage in the disease. Evidence that ╬▒Syn 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 ╬▒Syn plays a role in triggering the neurodegenerative process. ╬▒Syn'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 ╬▒Syn's effect on synaptic vesicle pool size and mobilization, ╬▒Syn being proposed as a negative or positive regulator of neurotransmitter release. In this review, we discuss the effect of ╬▒Syn 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 ╬▒Syn and on the spreading of ╬▒Syn-driven effects due to the presence of the protein in the extracellular milieu.

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Related in: MedlinePlus

Targets of extracellular ╬▒Syn. Extracellular soluble ╬▒Syn induces an increase in calcium entry by acting on the fluidity of the membrane or by activating N-type calcium channels that shift to cholesterol-poor domains of the membrane. Extracellular soluble ╬▒Syn clusters GRP78 at the plasma membrane, with ensuing activation of a pathway that leads to cofilin 1 phosphorylation.
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biomolecules-05-00865-f003: Targets of extracellular ╬▒Syn. Extracellular soluble ╬▒Syn induces an increase in calcium entry by acting on the fluidity of the membrane or by activating N-type calcium channels that shift to cholesterol-poor domains of the membrane. Extracellular soluble ╬▒Syn clusters GRP78 at the plasma membrane, with ensuing activation of a pathway that leads to cofilin 1 phosphorylation.

Mentions: ╬▒Syn monomers and oligomers might also exert their effect directly from the extracellular space on pre- and post-synaptic terminals. Diogenes et al. showed that, in rat hippocampal slices, prolonged exposure to ╬▒Syn oligomers determines an increase of basal synaptic transmission dependent on N-methyl-D-aspartate (NMDA) receptor activation. Moreover, they showed that the increase in NMDA receptor activity triggers an enhanced contribution of GluR1-containg ╬▒-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. In the long term, this non-physiological activity of AMPA receptors leads to impaired long-term potentiation (LTP) [182]. Melachroinou et al. used the application of naturally-secreted ╬▒Syn on rat cortical neurons and showed that extracellular ╬▒Syn can perturbs Ca2+ homeostasis with a mechanism that alters the fluidity property of the membrane [183]. Ronzitti and collaborators demonstrated that dysregulation of neurotransmitter release induced by monomeric extracellular ╬▒Syn depends on the activation of surface-exposed calcium channels. They provided evidence that extracellular ╬▒Syn, applied on rat cortical neurons or striatal slices, selectively activates N-type VOCCs, inducing neurotransmitter release. Moreover, they correlated the effect of ╬▒Syn with the reduction of membrane cholesterol and with the ensuing alteration in partitioning of N-type VOCCs, which move from raft to cholesterol-poor areas of the plasma membrane [184]. ╬▒SynÔÇÖs role in the regulation of axonal transport of synaptic vesicles [185] and of synaptic vesicle mobilization at the terminal might be mediated by a specific binding with proteins belonging to or associated with microtubules and microfilaments. Syn may interact with the MT-binding domain of protein tau [186], MT-associated protein 1B (MAP1B) [187] and 2 (MAP2) [188]. ╬▒Syn and actin has been observed to partially co-localize in neuronal cell lines [189]. ╬▒Syn can also influence the cytoskeleton of cultured neurons when applied to the extracellular milieu. Using a biochemical approach, Alim et al. showed that ╬▒Syn binds to heterodimeric tubulin and may seed ╬▒Syn fibril formation, an interaction capability that is lost by the mutant forms of ╬▒Syn [190]. Liu and collaborators demonstrated that application of wt ╬▒Syn to cultured primary rat cortical neurons leads to microtubule assembly and neurite outgrowth. The A30P and the A53T mutant forms do not show the same effect [191]. Various studies indicated a strong relationship between ╬▒Syn and the microtubule-associated protein tau in the neurodegenerative process [192,193]. The major function of tau is the stabilization of microtubule dynamics necessary for neurite outgrowth, morphogenesis, axonal transport and physiological neuronal function [194]. Gassowska et al. suggest that the interaction of ╬▒Syn with tau, increasing phosphorylation of tau by GSK-3╬▓, leads to microtubule destabilization [195]. Bellani et al. showed that the interaction of ╬▒Syn with a surface-exposed glucose-related protein of 78 kDa (GRP78) activates a signaling cascade that, acting on cofilin 1, affects the morphology and dynamics of the actin cytoskeleton. Downregulation of GRP78 abolishes the activity of exogenous ╬▒Syn, suggesting that it is the primary target of ╬▒Syn [196]. In the model in Figure 3 are shown the targets of extracellular ╬▒Syn acting from the extracellular space.


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

Emanuele M, Chieregatti E - Biomolecules (2015)

Targets of extracellular ╬▒Syn. Extracellular soluble ╬▒Syn induces an increase in calcium entry by acting on the fluidity of the membrane or by activating N-type calcium channels that shift to cholesterol-poor domains of the membrane. Extracellular soluble ╬▒Syn clusters GRP78 at the plasma membrane, with ensuing activation of a pathway that leads to cofilin 1 phosphorylation.
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00865-f003: Targets of extracellular ╬▒Syn. Extracellular soluble ╬▒Syn induces an increase in calcium entry by acting on the fluidity of the membrane or by activating N-type calcium channels that shift to cholesterol-poor domains of the membrane. Extracellular soluble ╬▒Syn clusters GRP78 at the plasma membrane, with ensuing activation of a pathway that leads to cofilin 1 phosphorylation.
Mentions: ╬▒Syn monomers and oligomers might also exert their effect directly from the extracellular space on pre- and post-synaptic terminals. Diogenes et al. showed that, in rat hippocampal slices, prolonged exposure to ╬▒Syn oligomers determines an increase of basal synaptic transmission dependent on N-methyl-D-aspartate (NMDA) receptor activation. Moreover, they showed that the increase in NMDA receptor activity triggers an enhanced contribution of GluR1-containg ╬▒-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. In the long term, this non-physiological activity of AMPA receptors leads to impaired long-term potentiation (LTP) [182]. Melachroinou et al. used the application of naturally-secreted ╬▒Syn on rat cortical neurons and showed that extracellular ╬▒Syn can perturbs Ca2+ homeostasis with a mechanism that alters the fluidity property of the membrane [183]. Ronzitti and collaborators demonstrated that dysregulation of neurotransmitter release induced by monomeric extracellular ╬▒Syn depends on the activation of surface-exposed calcium channels. They provided evidence that extracellular ╬▒Syn, applied on rat cortical neurons or striatal slices, selectively activates N-type VOCCs, inducing neurotransmitter release. Moreover, they correlated the effect of ╬▒Syn with the reduction of membrane cholesterol and with the ensuing alteration in partitioning of N-type VOCCs, which move from raft to cholesterol-poor areas of the plasma membrane [184]. ╬▒SynÔÇÖs role in the regulation of axonal transport of synaptic vesicles [185] and of synaptic vesicle mobilization at the terminal might be mediated by a specific binding with proteins belonging to or associated with microtubules and microfilaments. Syn may interact with the MT-binding domain of protein tau [186], MT-associated protein 1B (MAP1B) [187] and 2 (MAP2) [188]. ╬▒Syn and actin has been observed to partially co-localize in neuronal cell lines [189]. ╬▒Syn can also influence the cytoskeleton of cultured neurons when applied to the extracellular milieu. Using a biochemical approach, Alim et al. showed that ╬▒Syn binds to heterodimeric tubulin and may seed ╬▒Syn fibril formation, an interaction capability that is lost by the mutant forms of ╬▒Syn [190]. Liu and collaborators demonstrated that application of wt ╬▒Syn to cultured primary rat cortical neurons leads to microtubule assembly and neurite outgrowth. The A30P and the A53T mutant forms do not show the same effect [191]. Various studies indicated a strong relationship between ╬▒Syn and the microtubule-associated protein tau in the neurodegenerative process [192,193]. The major function of tau is the stabilization of microtubule dynamics necessary for neurite outgrowth, morphogenesis, axonal transport and physiological neuronal function [194]. Gassowska et al. suggest that the interaction of ╬▒Syn with tau, increasing phosphorylation of tau by GSK-3╬▓, leads to microtubule destabilization [195]. Bellani et al. showed that the interaction of ╬▒Syn with a surface-exposed glucose-related protein of 78 kDa (GRP78) activates a signaling cascade that, acting on cofilin 1, affects the morphology and dynamics of the actin cytoskeleton. Downregulation of GRP78 abolishes the activity of exogenous ╬▒Syn, suggesting that it is the primary target of ╬▒Syn [196]. In the model in Figure 3 are shown the targets of extracellular ╬▒Syn acting from the extracellular space.

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 (╬▒Syn)-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 ╬▒Syn have been identified as risk factors for idiopathic PD, pointing to the importance of wild-type (wt) ╬▒Syn dosage in the disease. Evidence that ╬▒Syn 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 ╬▒Syn plays a role in triggering the neurodegenerative process. ╬▒Syn'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 ╬▒Syn's effect on synaptic vesicle pool size and mobilization, ╬▒Syn being proposed as a negative or positive regulator of neurotransmitter release. In this review, we discuss the effect of ╬▒Syn 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 ╬▒Syn and on the spreading of ╬▒Syn-driven effects due to the presence of the protein in the extracellular milieu.

Show MeSH
Related in: MedlinePlus