The role of alpha-synuclein in neurotransmission and synaptic plasticity

Journal of Chemical Neuroanatomy 42 (2011) 242–248

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Review

The role of alpha-synuclein in neurotransmission and synaptic plasticity Furong Cheng a, Giorgio Vivacqua b, Shun Yu a,* a

Department of Neurobiology Key Laboratory of Neurodegenerative Diseases (Capital Medical University), Ministry of Education, Xuanwu Hospital of China Capital Medical University, 100053 Beijing, China b Department of Human Anatomy, Sapienza University, Rome 00161, Italy

A R T I C L E I N F O

A B S T R A C T

Article history: Received 11 October 2010 Received in revised form 7 December 2010 Accepted 7 December 2010 Available online 16 December 2010

Alpha-synuclein (a-syn), a synaptic protein richly expressed in the central nervous system, has been implicated in several neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies, which are collectively known as synucleinopathies. By contrast to the clear evidence for the involvement of a-syn in synucleinopathies, its physiological functions remain elusive, which becomes an impediment for revelation of its pathological mechanism. Since a-syn is richly expressed in presynaptic terminals and associated with synaptic vesicles, a large number of studies have been focused on revealing the potential functions of this protein in neurotransmission and synaptic plasticity. In this review article, we summarized recent advances for the role of a-syn in synaptic vesicle recycling, neurotransmitter synthesis and release, and synaptic plasticity. We discussed the possible relevance between the loss of normal a-syn functions in disease conditions and the onset of some neurodegenerative diseases. ß 2010 Elsevier B.V. All rights reserved.

Keywords: Alpha-synuclein Synucleinopathy Neurotransmission Synaptic plasticity Neuron

Contents 1. 2. 3.

4. 5. 6.

Molecular structure and functional characteristic of a-syn. . . . . . . . . . . . . . . Synaptic vesicle recycling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis, vesicular storage and release of neurotransmitters . . . . . . . . . . . . Transmitter synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Vesicular transmitter storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Transmitter release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Implications relevant to the etiopathogenesis of neurodegenerative diseases Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Alpha-synuclein (a-syn), a 140-amino acid protein richly expressed in presynaptic terminals in the central nervous system, has been implicated in the pathogenesis of several neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) (Ue´da et al., 1993; Spillantini et al., 1997; Baba et al., 1998; Gai et al., 1998; Spillantini et al., 1998; Recchia et al., 2004). In

* Corresponding author at: Department of Neurobiology, Beijing Institute of Geriatrics, Xuanwu Hospital of China Capital Medical University, 45# Changchun Street, Beijing 100053, China. Tel.: +86 10 8319 8890; fax: +86 10 8316 1294. E-mail address: [email protected] (S. Yu). 0891-0618/$ – see front matter ß 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jchemneu.2010.12.001

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all these diseases, fibrillated full-length a-syn or its partial fragments constitutes the major component of the characteristic pathological structure specific for each disease. Therefore, these diseases are also collectively known as synucleinopathies. The involvement of a-syn in synucleinopathies obtains further support by the fact that mutations and multiplications for the gene encoding a-syn can directly cause some types of synucleinopathies such as PD and DLB (Martı´ et al., 2003; Jellinger, 2008). By contrast to the clear evidence for the involvement of a-syn in neurodegenerative diseases, the normal functions of this protein remain elusive although a large number of studies have been made to reveal its potential physiological functions in the nervous system. In the present review article, we will summarize recent advances in the

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Fig. 1. Molecular structure and functional characteristic of a-syn. a-Syn is functionally divided into N-terminal (1–65aa), NAC (66–95aa), and C-terminal (96–140aa) domains. The N-terminal domain contains four of the seven KTKEGV motifs (blue color) and has three point mutation sites linked to autosomal dominant early-onset PD. The NAC domain, which encompasses the most hydrophobic residues, has additional KTKEGV motifs, promotes a-syn aggregation, with a phosphorylation site. The C-terminal domain exhibits chaperone activity that tends to decrease protein aggregation, and has one phosphorylation site and three nitration sites.

research of a-syn functions, with specific attention paid to synaptic vesicle recycling, neurotransmitter synthesis and release, and synaptic plasticity. We will discuss the possible relevance between the loss of normal a-syn functions in disease conditions and the onset of some neurodegenerative diseases. 1. Molecular structure and functional characteristic of a-syn

a-Syn belongs to the synuclein family that also consists of band g-syns (Clayton and George, 1998). Although all the synucleins are present in the human brain, only a-syn is shown to be associated with the pathological structures in neurodegenerative conditions (Spillantini et al., 1997; Baba et al., 1998; Spillantini et al., 1998; Tu et al., 1998). The human a-syn is a 140-amino acid protein, initially found and named as NACP, i.e. the precursor of the non-Ab-component of AD amyloid. The non-Ab-component is also known as NAC, which is a central hydrophobic peptide of human a-syn (Ue´da et al., 1993). Sequence analysis suggests that a-syn consists of three distinct regions: the N-terminal amphipathic region (residues 1–65), the central hydrophobic NAC region (residues 66–95), and the C-terminal acidic region (residues 96–140) (Clayton and George, 1998) (Fig. 1). The N-terminal half of a-syn contains seven imperfect 11-mer repeats with a highly conserved hexamer motif KTKEGV, among which approximately 4 are located in the highly basic N-terminal region of the protein, and 3 in the highly acidic and hydrophobic NAC region (George et al., 1995; Davidson et al., 1998). The 11-mer repeats make up a conserved apolipoprotein-like class-A2 helix that mediates the binding of a-syn to phospholipid vesicles (Segrest et al., 1990; Davidson et al., 1998). The lipid binding is accompanied by a large shift in protein secondary structure, from around 3% to over 70% ahelix, and is thought to be critical for the normal function of a-syn

(Perrin et al., 2000). Several lines of evidence support the membrane-binding capacity of the N-terminal region. For example, mutations in this region were shown to perturb plasma membrane localization of the protein in yeast (Volles and Lansbury, 2007). Moreover, deletions of single exons within the lipid-binding N-terminal region (exons 2, 3, and 4) or the PDassociation mutation A30P was found to partially disrupt the localization of a-syn at presynaptic terminals, resulting in increased diffuse labeling of axons (Yang et al., 2010). Furthermore, the A53T mutant was demonstrated to exhibit normal presynaptic enrichment, but with the transport velocity decreased relative to the other variants (Yang et al., 2010). Finally, some evidence indicated that deletion of lipid-binding exons 2–4 resulted in a decreased number of motile, axonal a-syn-containing particles without affecting instantaneous velocity of those particles (Yang et al., 2010). Except the membrane-binding activity, the 11-mer imperfect repeats in the N-terminal region were shown to mediate rapid membrane translocation of a-syn in a mechanism distinct from normal endocytosis (Ahn et al., 2006). The central hydrophobic NAC region of a-syn was initially identified from the AD brains as the non-b-amyloid component of the AD amyloid (Ue´da et al., 1993). In vitro studies suggest that the NAC region is essential for the aggregation and toxicity of a-syn (Kim et al., 2009). NAC may be a common target or trigger for amyloid plaque formation in AD (Han et al., 1995). For example, the NAC peptide can not only seed the amyloid formation of b-amyloid protein but also is seeded by the b-amyloid protein to form the NAC amyloid. The NAC can also form amyloid after being cleaved out of its precursor and may be a crucial factor in amyloidosis in the AD brain (Iwai et al., 1995). The major difference between a-syn and b-syn is that the b-syn lacks the middle segment of the NAC region (residues 73–83) of the a-syn

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(Jakes et al., 1994). In accordance with this, b-syn does not aggregate; instead, it prevents a-syn from aggregation, further suggesting that the NAC region is responsible for a-syn aggregation. As mentioned above, the 6th and 7th 11-mer repeat sequences in the NAC region have a strong effect on a-syn folding and the 6th repeat sequence has a particularly strong influence on the propensity of a-syn to aggregate and fibrillate (Sode et al., 2006). The C-terminal region of a-syn is organized as 16 amino acid repeats, which could be important for Ca2+ binding (Nielsen et al., 2001). This region is rich in acidic amino acids and shows significant difference in primary sequences among a-, b-, and g-syns (Clayton and George, 1999). The C-terminal region seems to play a role in preventing a-syn aggregation. This speculation comes from the fact that the C-terminal-region-truncated form of a-syn (residues 1–120) is more prone to form filaments than the full length protein (Crowther et al., 1998). In addition, the C-terminal region of a-syn appears to have chaperone activity. Results with synthetic C-terminal peptides and C-terminal deletion mutants suggest that the second acidic repeat (residues 125–140) of a-syn is important for the chaperone activity, and C-terminal deletion leads to the facilitated aggregation with the elimination of chaperone activity (Kim et al., 2002). Modifications of this second repeat region are implicated in the aggregation process and protein interactions of a-syn. For example, phosporylation of Ser129 or nitration of Tyr125, Tyr133, and Tyr136 promote the formation of a-syn filaments or oligomers (Giasson et al., 2000; Souza et al., 2000; Fujiwara et al., 2002). a-Syn 112 lacking exon 5 (aa 103–130) in the C-terminal half shows an enhanced tendency to aggregate and fibrillize (Crowther et al., 1998). The above results suggest that the C-terminus of a-syn can play a role of an intramolecular chaperone by preventing a-syn from fibrillization (Kim et al., 2002). Another potential function of the C-terminal region is the protective role against oxidative stress. This protective role could be demonstrated by observations that truncation of a-syn exaggerates the susceptibility of dopaminergic cells to oxidative damage (Kanda et al., 2000) and the protective role of a-syn against oxidative stress requires a-syn C-terminal

Fig. 2. Schematic diagram for the potential functions of a-syn in the regulation of synatic vesicle recycling. a-Syn may regulate the trafficking of synaptic vesicles from the distal reserve pool to the readily releasable pool as well as the docking, priming, fusion of the synaptic vesicles. In addition, a-syn can also regulate the endocytosis and recycling of the synaptic vesicles after release of neurotransmitters. SV: synaptic vesicle. RP: reserve pool. RRP: readily releasable pool.

domain without dependence on the presence of the pathogenetic mutations A30P and A53T (Albani et al., 2004). 2. Synaptic vesicle recycling Although a-syn is distributed to almost all subcellular compartments, it is particularly enriched in the presynaptic terminals where it is loosely associated with the distal reserve pool of synaptic vesicles (Lavedan, 1998; Yu et al., 2007). The high presynaptic concentration of a-syn and its association with synaptic vesicles suggest a physiological role of the protein in the regulation of synaptic transmission as well as synaptic vesicle recycling. Evidence obtained indicates that a-syn is involved in almost every step of synaptic vesicle recycling, including trafficking, docking, fusion, and recycling after exocytosis (Fig. 2). For example, suppression of a-syn expression in cultured neurons reduced the distal reserve pool of synaptic vesicles (Murphy et al., 2000) and a-syn knock-out mice exhibited an increase in synaptic paired-pulse facilitation, suggesting a-syn to act as an activitydependent, negative regulator of transmitter release that would restrict the traffic of synaptic vesicles from the reserve pool to the release sites (Abeliovich et al., 2000; Cabin et al., 2002). These results appear consistent with the increased refilling of the readily releasable pool observed in the striatum of mice null for the a-syn gene or expressing its A30P mutated form, which also shows a reduced size of the reserve pool (Yavich et al., 2004, 2006). To support the results obtained from the a-syn gene null models, overexpression of a-syn also demonstrates the role of a-syn in synaptic vesicle recycling. For instance, overexpression of a-syn in PC12 cells resulted in an accumulation of ‘‘docked’’ vesicles at the synapse (Larsen et al., 2006); modest overexpression of a-syn in the range predicted for gene multiplication and in the absence of overt toxicity markedly inhibited neurotransmitter release by reducing the readily releasable and recycling synaptic vesicle pools as well as impairing the reclustering of synaptic vesicles after endocytosis (Nemani et al., 2010). Several potential mechanisms have been proposed for the role of a-syn in the regulation of synaptic vesicle recycling. First, the action of a-syn on synaptic vesicle recycling may be partially mediated through its ability to inhibit the activity of phospholipase D2 (PLD2). PLD2 is a 106-kDa protein that is localized to the plasma membrane and is shown to participate in the regulation of vesicle trafficking and both endo- and exocytosis (Cockcroft, 2001). a-Syn has been shown to be able to bind with PLD2 and directly inhibit its activity (Ahn et al., 2002). In addition, a-syn may indirectly inhibit PLD2 activity through binding to proteins such as 14-3-3 proteins, protein kinase C, BAD, and Erk, that act as potent inhibitors of PLD2 in vitro experiments (Jenco et al., 1998). Second, a-syn may regulate synaptic vesicle recycling by affecting actin polymerization. Modulation of the vesicle release cycle by actin has been proposed to take place by multiple mechanisms. Actin microfilaments could provide tracks along which vesicles travel to reach their targets at the terminal, carrying them ahead by waves of actin polymerization; actin could also work as a physical barrier opposing exocytosis, binding synaptic vesicles and hindering their movement; on the other hand, actin has a scaffolding role and is required to cluster molecular complexes necessary for vesicle fusion at the release sites (Bellani et al., 2010). Some recent data indicate that a-syn appears to modulate the state of actin polymerization depending on the intracellular Ca2+ concentration in the pre-synaptic terminal, playing a role in the regulation of vesicle exit from the reserve pool and in their trafficking to the active zone, as well as in the regulation of their exocytosis and recycling (Bellani et al., 2010). Third, a-syn may act as a molecular chaperone to regulate synaptic vesicle recycling by assisting in the

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folding and refolding of synaptic proteins called SNAREs (the soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptors) (Bonini and Giasson, 2005). SNAREs are protein complex consisting of synaptobrevin, syntaxin, and SNAP25 and play a role in vesicle priming, transferring of docked vesicles into an exocytosis-competent state, and vesicle fusion to the membrane (Goda, 1997). Analysis of cysteine-string protein a (CSPa)-deficient mice suggests that this protein may aid in the folding and refolding of SNARE proteins and up-regulation of a-syn can compensate for the loss of CSPa activity, restoring SNARE complexes to their correct levels and suppressing presynaptic degeneration, motor dysfunction, and death of mice lacking CSPa (Chandra et al., 2005). 3. Synthesis, vesicular storage and release of neurotransmitters 3.1. Transmitter synthesis The effect of a-syn on the synthesis of neurotransmitters is mainly based on observations on dopaminergic neurons. Evidence obtained so far strongly support the notion that a-syn inhibits dopamine (DA) synthesis by regulation of the expression and activity of tyrosine hydroxylase (TH), a rate-limiting enzyme for DA synthesis in dopaminergic neurons. a-Syn was shown to physically bind with TH and inhibit the activity of the enzyme (Perez et al., 2002). In a-syn transgenic mice and a-syn transfected dopaminergic neurons, overexpression of a-syn was found to inhibit TH activity and DA synthesis (Masliah et al., 2000; Kirik et al., 2002) as well as TH expression (Baptista et al., 2003; Yu et al., 2004). By contrast, down-regulation of a-syn enhanced TH activity and DA synthesis (Liu et al., 2008). In accordance with the observations on the experimental models, studies in human and primate brains showed that aging-related increase in neuronal asyn expression in the substantia nigra was negatively correlated to the expression of TH, further indicating that a-syn may inhibit TH expression (Chu and Kordower, 2007). Inhibition of TH activity by a-syn appears related to the altered state of TH phosphorylation. Previous studies showed that phosphorylation of critical serine residues (40, 31 and 19) in the N-terminus of TH was associated with activation of the enzyme (Campbell et al., 1986; Haycock, 1990), which could be reversed by protein phosphatase 2A (PP2A) (Dunkley et al., 2004), an important enzyme required for dephosphorylation of TH. Several lines of evidence suggest that a-syn can reduce the phosphorylation of TH, bind with TH in a dephosphorylated state, and maintain TH in an inactive form (Perez et al., 2002; Peng et al., 2005; Wu et al., 2009; Lou et al., 2010). It seems that only the wild type a-syn has the ability to inhibit TH activity and the a-syn phosphorylated at Ser-129 loses the ability (Wu et al., 2009; Lou et al., 2010), suggesting a loss of the function for the phosphorylated a-syn to inhibit the phosphorylation of TH. 3.2. Vesicular transmitter storage Neurotransmitters are stored in vesicles after being synthesized. The entry of neurotransmitters into the vesicles is mediated by special transporter on the vesicular membrane. In dopaminergic neurons, the entry of dopamine transmitters is mediated by vesicular monoamine transporter 2 (VMAT2) (Eiden, 2000; Parsons, 2000; Weihe and Eiden, 2000). Using the yeast-two hybrid assay, Dean et al. (2007) demonstrate that a-syn interacts with VMAT2 and regulates activity of the transporter. Overexpression of A53T mutant a-syn in differentiated MESC2.10 cells resulted in down-regulation of the vesicular DA transporter (VMAT2) and enhancement of the cytoplasmic DA and superoxide, suggesting that mutant a-syn can lead to an impairment in

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vesicular DA storage and consequent accumulation of DA in the cytosol (Lotharius et al., 2002). Knockdown of a-syn increased the density of VMAT2 molecules per vesicle by 2.8-fold. In addition, up-regulation of a-syn expression inhibits the activity of VMAT2, thereby interrupting DA homeostasis and resulting in dopaminergic neuron injury in Parkinson’s disease (Guo et al., 2008). 3.3. Transmitter release The effect of a-syn on neurotransmitter release has been demonstrated in both the a-syn gene null and over-expression conditions. The role of a-syn in neurotransmitter release is mainly based on its regulation of synaptic vesicle recycling. In a-syn / mice, the nigrostriatal terminals displayed a standard pattern of DA discharge and reuptake in response to simple electrical stimulation but an increased release with paired stimuli with a concurrent reduction in striatal DA and an attenuation of DAdependent locomotor response to amphetamine (Abeliovich et al., 2000). These findings suggest that a-syn is an essential presynaptic, activity-dependent negative regulator of DA neurotransmission possibly due to the aforementioned restriction of the traffic of synaptic vesicles from the reserve pool to the release sites (Abeliovich et al., 2000). In another study, it was shown that mice with a-syn null mutation demonstrated a permanent increase of the vesicle refilling rate in the readily releasable pool, which maintained stable dopamine release during stimulation in contrast to a decline of dopamine release in other animals (Yavich et al., 2004). Regulation of neurotransmitter release by a-syn appears not restricted to DA transmission. The release of some other neurotransmitters was also shown to be regulated by a-syn. For example, field recording of CA1 synapses in hippocampal slices from the a-syn knock-out mice demonstrated significant impairments in synaptic response to a prolonged train of repetitive stimulation (12.5 Hz, 300 pulses) capable of depleting docked as well as reserve pool vesicles (Cabin et al., 2002). Experiments in transgenic mice with modified or absent a-syn revealed that a-syn mutation A30P abolished the normal norepinephrine mobilization. There were no compensatory mechanisms available in the norepinephrine presynaptic terminals (Li et al., 2004). In contrast, deletion of mouse a-syn is compensated for by increased vesicle transport from the storage pool, further indicating that the important role of a-syn in neurotransmitter mobilization is not limited to dopaminergic terminals (Yavich et al., 2006). Lack of asyn also decreased glutamate release by impairing mobilization of glutamate from the reserve pool (Gureviciene et al., 2007). The altered neurotransmitter release observed in the a-syn overexpressed models is also attributed to the regulation of the synaptic vesicle recycling by a-syn. 4. Synaptic plasticity

a-Syn is enriched at synaptic terminals in brain regions that display synaptic plasticity and is specifically up-regulated in a discrete population of presynaptic terminals of the songbird brain during a period of song-acquisition-related synaptic rearrangement (Hartman et al., 2001). These observations suggest a potential role of a-syn in synaptic plasticity. A number of in vitro and in vivo studies using a-syn null and over-expression models have indicated that a-syn may participate in the modulation of both short-term and long-term synaptic plasticity. Various brain regions have been investigated in revealing the role of a-syn in synaptic plasticity, which include nigrostriatal pathway, corticostriatal pathway, dentate gyrus perforant pathway, mossy fiber-CA3 pathway, and Schaffer collaterals-CA1 pathway (Abeliovich et al., 2000; Steidl et al., 2003; Gureviciene et al., 2007, 2009; Watson et al., 2009). However, differential effects have been observed. For

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example, short-term synaptic plasticity studies of corticostriatal slices from both a-syn over-expressing mice and ‘‘knock-out’’ mice showed that only elevated amounts of human a-syn reliably induced paired-pulse facilitation in the dorsolateral region of the striatum (Watson et al., 2009). In contrast, some previous reports showed paired-pulse depression or reduced paired-pulse facilitation in either the dentate gyrus perforant pathway or the mossy fiber-CA3 pathway of hippocampus from transgenic mice expressing human a-syn or a variant a-syn with the A30P mutation (Steidl et al., 2003; Gureviciene et al., 2007). The role of a-syn in long-term synaptic plasticity was observed in hippocampal neuronal cultures, showing that a-syn may participate in the induction of long-lasting potentiation of synaptic transmission in this cell model (Liu et al., 2004; Liu et al., 2007). In corticostriatal pathways, high-frequency stimulation induced a presynaptic form of long-term depression solely in the a-syn over-expressed mice rather than a-syn deficient mice or wild type mice (Watson et al., 2009). In another study on dentate gyrus perforant pathway, a-syn accumulation in aged A30P mice but not in aged wild-type mice was found to lead to a long-term depression of synaptic transmission after a stimulation protocol that normally induces long-term potentiation (Gureviciene et al., 2009), although a longterm potentiation was induced in same transgenic adult mice in mossy fibers-CA3 synapses (Gureviciene et al., 2007). The inconsistent results obtained for the effects of a-syn on synaptic plasticity could be ascribed to the experimental models used and the brain regions investigated, and may also reflect the complexity of the regulation of synaptic plasticity. The mechanism underlying the modulation of a-syn in synaptic plasticity appears to be related to the altered release probability of neurotransmitters through regulation of synaptic vesicle mobilization or trafficking from the reserve pool to the readily releasable pool. Again, different effects of a-syn have been observed on the release of neurotransmitters. While some of studies demonstrate a negative role of a-syn for the mobilization of synaptic vesicles from the reserve pool to the readily releasable pool, which is accompanied by the reduced release of neurotransmitter (Abeliovich et al., 2000; Steidl et al., 2003; Yavich et al., 2004, 2006; Larsen et al., 2006; Watson et al., 2009), some others support a positive role of the protein that facilitate the release of neurotransmitters, with an increase of vesicle availability for release (Steidl et al., 2003; Liu et al., 2004, 2007; Gureviciene et al., 2007, 2009). The different effects of a-syn on the release probability of neurotransmitters are compatible with the differential regulations of the protein on synaptic plasticity in various conditions.

aggregation of a-syn would be predicted to increase DA release from the surviving nigral DA neurons and may slow the progression of PD without serious deleterious effects. Synaptic plasticity has often been argued to play an important role in learning and memory (Martin et al., 2000). Because of the presence of cognitive abnormalities and dementia in many patients affected by synucleinopathies, it is possible that impaired synaptic plasticity due to the loss of a-syn function could underlie the cognitive abnormalities that are often present in the natural history of those diseases. For example, studies on the ASOTg mice overexpressing human a-syn can demonstrate the potential involvement of a-syn in some early pathological changes in PD. These mice showed accumulation of protease resistant a-syn aggregates and deficits of motor behavior in the absence of detectable neuron cell loss (Fleming et al., 2004; Fernagut et al., 2007). In addition, these mice exhibited altered short term and long-term presynaptic forms of synaptic plasticity (Watson et al., 2009), consistent with a potential decrease in glutamate release from corticostriatal terminals, which would decrease long-term excitatory synaptic transmission between the cortex and striatum, thereby blocking the main inhibitory outputs from the striatum to the substantia nigra and globus pallidus (Graybiel et al., 1981; Haber, 2003). This would lead to disinhibition of the striatalthalamo-cortical loop, which producing hypokinetic effects and reducing overall movement, the characteristic of PD. In addition to PD, it is also possible that the loss of a-syn function may be also responsible for the cognitive problems in Parkinson’s disease with dementia (PDD) and dememtia with Lewy bodies (DLB). As have aforementioned, a-syn may play a role in the regulation of synaptic plasticity in several pathways in the hippocampus (Steidl et al., 2003; Gureviciene et al., 2007), which are involved in the cognitive decline in PDD and DLB (Tiraboschi et al., 2000; Aarsland et al., 2004). The accumulation of a-syn aggregates has been reported in the hippocampus in PDD and DLB (Nakashima-Yasuda et al., 2007). It is possible that abnormal accumulation of a-syn may make it lose the function in the regulation of synaptic plasticity, being a potential cause for the declined cognition. Since a-syn can compensate for the loss of CSPa activity, restoring SNARE complexes to their correct levels and suppressing presynaptic degeneration, motor dysfunction, and death of mice lacking CSPa (Chandra et al., 2005), it is possible that loss of a-syn function by mutations, modifications, and aggregation may accelerate neurodegeneration observed for PD and other synucleinopathies. 6. Summary

5. Implications relevant to the etiopathogenesis of neurodegenerative diseases

a-Syn has been shown to be involved in almost all the processes related to DA synthesis and release. As described above, the presence of a-syn in DA neurons in normal conditions tends to tone down the amount of cytoplasmic DA at nerve terminals (Sidhu et al., 2004; Yu et al., 2005), thereby limiting its conversion to highly reactive oxidative molecules. In addition, a-syn may affect the DA release as a negative regulator at the synaptic terminals of DA neurons (Abeliovich et al., 2000). It can be speculated that mutations in the a-syn gene or abnormal aggregation in disease conditions may lead to the loss of normal a-syn functions. This will favor the production of the highly reactive oxidative species in the cytoplasm of neurons through relief of the limitation mechanism exerted by a-syn, which in turn exacerbate a-syn modification and aggregation (Yu et al., 2005). Since a-syn functions in the regulation of DA release, it represents a potential therapeutic target for PD as well as other movement and DA psychiatric disorders. Disruption of the synthesis, function, or, possibly, the

Although a-syn is implicated in several neurodegenerative diseases known as synucleinopathies, where a-syn aggregation shares the common features, there is ample evidence supporting that in the normal brain a-syn is not neurotoxic but participates in various functions associated with neurotransmission and synaptic plasticity, including synaptic vesicle recycling, neurotransmitter synthesis and release, and synaptic plasticity. Mutations and aggregation of a-syn may lead to the loss of a-syn normal functions that would initiate the pathological processes in the synucleinopathies. Thorough identification of the functions of asyn in regulation of neurotransmission and synaptic plasticity will shed a light on the mechanisms underlying its pathological roles. Acknowledgements The authors are supported by grants from the National High Technology Research and Development Program (‘‘863’’Program) of China (2006AA02A408), the National Basic Research Program (‘‘973’’ Program) of China (2011CB504101), and the National

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