These two exciting articles provide significant momentum for the field of Parkinson's disease research. The Singleton/Farrer paper cements the role of α-synuclein as a central player in the pathogenesis of PD. Their discovery of an elevated gene dosage effect of the snca gene in the Iowa kindred bears obvious resemblance to the elevated gene dosage of the APP gene conferred by trisomy 21 and its role in the pathogenesis of Alzheimer's disease.

Omar el Agnaf's work raises many intriguing questions. One, whether α-synuclein levels in body fluids of humans may be used as a biomarker for the disease, and two, as to the precise source of α-synuclein in peripheral blood, which may be platelets. In that sense, el-Agnaf's work also shows intriguing parallels to Alzheimer's disease, as APP isoforms, including of amyloid β-protein, have been found in peripheral blood and CSF. These findings are also of possible relevance to multiple system atrophy, a PD-like illness in which α-synuclein deposits are predominantly found in oligodendroglia, a type of cell that usually does not express...  Read more

These two exciting articles provide significant momentum for the field of Parkinson's disease research. The Singleton/Farrer paper cements the role of α-synuclein as a central player in the pathogenesis of PD. Their discovery of an elevated gene dosage effect of the snca gene in the Iowa kindred bears obvious resemblance to the elevated gene dosage of the APP gene conferred by trisomy 21 and its role in the pathogenesis of Alzheimer's disease.

Omar el Agnaf's work raises many intriguing questions. One, whether α-synuclein levels in body fluids of humans may be used as a biomarker for the disease, and two, as to the precise source of α-synuclein in peripheral blood, which may be platelets. In that sense, el-Agnaf's work also shows intriguing parallels to Alzheimer's disease, as APP isoforms, including of amyloid β-protein, have been found in peripheral blood and CSF. These findings are also of possible relevance to multiple system atrophy, a PD-like illness in which α-synuclein deposits are predominantly found in oligodendroglia, a type of cell that usually does not express significant amounts of the snca gene product.

View all comments by Michael Schlossmacher

This is a key paper in establishing the role of synuclein and synuclein misfolding in Parkinson disease. It is analagous to the situation in AD, where there is trisomy 21 and, more recently, focal triplications of APP.

View all comments by David Holtzman

Further evidence that α-synuclein gene dosage mutations are rare
In this simple paper, the authors screened for SNCA gene dosage mutations in a cohort of 190 unrelated PD patients who presented with a positive family history. No mutations were identified, consistent with previous data (Johnson et al., 2004). While this shows that SNCA multiplication mutation is a rare cause of Parkinson disease, the authors argue that this does not preclude a role for α-synuclein expression and clearance in the pathogenesis of Parkinson disease. The authors briefly discuss the growing evidence that α-synuclein load is a factor in the etiology of PD.

View all comments by Andrew Singleton

In recent months, the field of Parkinson disease (PD) has seen several exciting research developments. Three papers address increased α-synuclein (αS) expression in the human brain as a neurotoxic event in the pathogenesis of this disorder; one additional paper identifies a probable susceptibility gene for sporadic PD, and a fifth highlights the importance of the protective function of the parkin gene in an in vivo rat model of αS-mediated toxicity.

As a mostly presynaptic protein, αS is transcribed from five of the six exons of the SNCA gene and represents one of the most abundant proteins found in the adult nervous system. In the first of a series of five publications, Chartier-Harlin et al. last fall reported that a rare duplication event of the SNCA gene on one chromatid of chromosome 4, leading to a total of three SNCA gene copies, lies at the root of an aggressive Parkinsonian phenotype that encompasses early-onset PD with cognitive and autonomic dysfunction transmitted in an autosomal-dominant fashion. This report further...  Read more

In recent months, the field of Parkinson disease (PD) has seen several exciting research developments. Three papers address increased α-synuclein (αS) expression in the human brain as a neurotoxic event in the pathogenesis of this disorder; one additional paper identifies a probable susceptibility gene for sporadic PD, and a fifth highlights the importance of the protective function of the parkin gene in an in vivo rat model of αS-mediated toxicity.

As a mostly presynaptic protein, αS is transcribed from five of the six exons of the SNCA gene and represents one of the most abundant proteins found in the adult nervous system. In the first of a series of five publications, Chartier-Harlin et al. last fall reported that a rare duplication event of the SNCA gene on one chromatid of chromosome 4, leading to a total of three SNCA gene copies, lies at the root of an aggressive Parkinsonian phenotype that encompasses early-onset PD with cognitive and autonomic dysfunction transmitted in an autosomal-dominant fashion. This report further strengthens the importance of the gene dosage effect of the SNCA gene in the pathogenesis of rare familial forms of the disorder, which was previously raised by two independent reports of triplication events in the SNCA gene (leading to a total of four copies) (Singleton et al., 2003; Farrer et al., 2004). Intriguingly, the copy number of the SNCA gene, its resultant transcription, and the severity of the phenotype appeared to correlate with the gene dosage in all these cases. That is consistent with the concept of a toxic gain-of-function effect of wild-type αS in this class of disorders that are generally referred to as "synucleinopathies."

Gispert et al., 2005 demonstrated that gene dosage changes were not found as the underlying mutant genotype in a European cohort of familial PD phenotypes from Germany, Portugal, and the former Yugoslavia. Thus, as expected, these multiplication events of the SNCA gene are (and will likely remain) rare and isolated contributors to the phenotype of PD. Even so, they may be just as significant to the understanding of PD pathology as APP gene dosage in Down syndrome is to the development of Alzheimer disease pathology.

The third paper discussed in this comment fits in logical succession with the body of work on gene dosage. It revisits the genetics of the SNCA promoter as a susceptibility factor for sporadic (not familial) PD (Pals et al., 2004). In it, Matt Farrer, Christine van Broeckhoven, and colleagues first confirmed previous reports that had postulated an association between the SNCA promoter and sporadic PD. In addition, the authors also characterized a "minimum promoter haplotype" of 15,338 bp that is overrepresented in their cohort of 175 patients from Belgium and that may act as a susceptibility factor for PD development. The implication from such a positive association of a distinct SNCA promoter haplotype with sporadic PD is that the expression levels of the αS protein would be increased in vivo in contrast to an allele carrying a promoter haplotype not associated with PD. This hypothesis can now be tested in detail in cellular promoter activity assays, as used, for example, by Chiba-Falek and Nussbaum in the past.

A fourth study provides additional genetic input to the list of susceptibility factors in sporadic PD. Ellen Sidransky and her colleagues at the NIH (Varkonyi et al., 2003) first observed Parkinsonism in a subgroup of patients with a genetically defined glycosphingolipid storage disorder called Gaucher’s disease. Last November, Aharon-Peretz et al. added further evidence to this association when they reported a statistically significant occurrence of gene mutations in the glucocerebrosidase-encoding gene (GBA) among Ashkenazi Jews with sporadic PD who showed no signs of Gaucher’s disease (Aharon-Peretz et al., 2004). In their study, 31 percent of sporadic PD patients had either one or two mutant GBA alleles, in contrast to only 4 percent of people with sporadic Alzheimer disease. The underlying molecular pathway between altered GBA genotypes and the development of PD remains to be determined, in particular whether glucocerebrosidase activity (which, when absent, results in Gaucher’s disease phenotype) intersects with other known PD-associated gene products.

Lastly, the fifth paper, by Patrick Aebischer’s group, provides an intriguing animal model by pairing the authors’ previously developed toxic in vivo model of human αS overexpression by lentiviral delivery with the neuroprotective effects of the concomitant delivery of wild-type parkin (LoBianco et al., 2004). Numerous studies have linked the latter protein to monogenic forms of PD in a loss-of-function type (e.g., Hedrich et al., 2002). Many researchers see overexpression of neural parkin as a valid therapeutic goal to confer protection of dopaminergic cells from PD-related insults. The Aebischer group demonstrated just that by showing a significant reduction of mutant, human αS (A30P)-induced neuronal loss in the nigrostriatal pathway by parkin overexpression. In association with this neuroprotection, they observed an increase in αS-positive inclusions. It remains unknown which mechanism underlies the significant protection of the dopamine-producing cells in this rat model, and whether parkin intersects with αS metabolism directly or indirectly. Even so, the authors suggested that these results were consistent with a contributing role for parkin in inclusion (Lewy body) formation in vivo, as has been suggested by past immunohistochemical studies in human PD tissue (Schlossmacher et al., 2002).

Together, these studies highlight three issues:

1. steady-state levels of αS are important in the pathogenesis of PD in the adult human brain, and multiple pathways potentially contribute to its control;

2. an important question is whether the nucleotide sequence, the rate of transcription, or the protein product of the SNCA gene could serve as a biomarker for PD;

3. the concept of increased parkin expression is being validated as a therapeutic target; this goal is of equal importance to the desired downregulation of α-synuclein expression in vivo.

View all comments by Michael Schlossmacher

Our goal in this study was to try connecting the dots between two key pathologic events: modestly elevated α-synuclein levels within the neuron and the ultimate synaptic dysfunction. We used a cell-biological approach that allowed us to analyze and quantify thousands of α-synuclein overexpressing boutons. Based on the data, we suggest a cascade of pathologic events initiated by modest elevations of α-synuclein and culminating in synaptic damage. Studies by Nemani et al. focus on the effects of elevated α-synuclein on specific steps within the synaptic release/recycling machinery by directly imaging the synaptic cycle in α-synuclein transfected neurons.

First, it is important to emphasize that using a variety of methods, both studies show at a single-neuron level that the overall synaptic defect induced by modestly elevated α-synuclein is an inhibition of neurotransmitter release. Thus, collectively, these studies provide a firm pathologic role that can be attributed to α-synuclein overexpression. The studies by Nemani et al. also show a dose-dependent effect of excessive...  Read more

Our goal in this study was to try connecting the dots between two key pathologic events: modestly elevated α-synuclein levels within the neuron and the ultimate synaptic dysfunction. We used a cell-biological approach that allowed us to analyze and quantify thousands of α-synuclein overexpressing boutons. Based on the data, we suggest a cascade of pathologic events initiated by modest elevations of α-synuclein and culminating in synaptic damage. Studies by Nemani et al. focus on the effects of elevated α-synuclein on specific steps within the synaptic release/recycling machinery by directly imaging the synaptic cycle in α-synuclein transfected neurons.

First, it is important to emphasize that using a variety of methods, both studies show at a single-neuron level that the overall synaptic defect induced by modestly elevated α-synuclein is an inhibition of neurotransmitter release. Thus, collectively, these studies provide a firm pathologic role that can be attributed to α-synuclein overexpression. The studies by Nemani et al. also show a dose-dependent effect of excessive α-synuclein, and strongly implicate the N-terminus of α-synuclein in the pathogenesis. However, while Nemani et al. posit an exclusive impairment of “reclustering” of synaptic vesicles as the solitary defect induced by excessive α-synuclein upon the presynaptic apparatus, our studies suggest that that the effects of elevated α-synuclein on the synaptic apparatus are diverse, including defects in pathways involved in both endo- and exocytosis.

The experiments by Nemani et al. are direct and convincing, and it is possible that a “reclustering” defect is a major pathology induced by excessive α-synuclein, with other minor defects on other aspects of the synaptic machinery as well. As relative newcomers to the field, we have no favorite hypothesis on how α-synuclein causes inhibition of neurotransmitter release. However, given our data and other α-synuclein studies in yeast and mice, and the well-known pleiotropic effects of other well-studied proteins implicated in neurodegeneration (tau, amyloid), we favor the view that α-synuclein has diverse effects on the synaptic release apparatus.

View all comments by Subhojit Roy

The background for our work is that α-synuclein normally localizes to the axon terminal of essentially all neurons, but its role, if any, in neurotransmitter release has remained very unclear. In general, knockout mice have shown either no effect or conflicting effects on synaptic transmission. Increased expression of α-synuclein causes Parkinson disease (PD)—duplication and triplication of the wild-type gene cause severe familial PD, and the protein accumulates in all sporadic PD. In light of this, we wondered what overexpression might do to synaptic transmission. This seemed particularly interesting because overexpression of wild-type α-synuclein in mice actually fails to produce degeneration, and an effect on transmitter release would be easier to interpret in the absence of toxicity.

To understand how α-synuclein affects neurotransmitter release, we used a combination of primary neuronal culture and genetic manipulation in mice. The reason is that, although culture is very powerful to dissect molecular mechanism, it suffers from greater variability and has more potential...  Read more

The background for our work is that α-synuclein normally localizes to the axon terminal of essentially all neurons, but its role, if any, in neurotransmitter release has remained very unclear. In general, knockout mice have shown either no effect or conflicting effects on synaptic transmission. Increased expression of α-synuclein causes Parkinson disease (PD)—duplication and triplication of the wild-type gene cause severe familial PD, and the protein accumulates in all sporadic PD. In light of this, we wondered what overexpression might do to synaptic transmission. This seemed particularly interesting because overexpression of wild-type α-synuclein in mice actually fails to produce degeneration, and an effect on transmitter release would be easier to interpret in the absence of toxicity.

To understand how α-synuclein affects neurotransmitter release, we used a combination of primary neuronal culture and genetic manipulation in mice. The reason is that, although culture is very powerful to dissect molecular mechanism, it suffers from greater variability and has more potential for artifact than analysis in vivo. By optical imaging, we found that α-synuclein specifically inhibits synaptic vesicle exocytosis, in particular, the extent of exocytosis rather than the rate, with no effect on synaptic vesicle endocytosis. We used a variety of experimental approaches (FM dyes, pHluorin reporter) to document a selective reduction in the size of the synaptic vesicle recycling pool, with no change in the total number of synaptic vesicles. Since previous work has suggested differences between dopamine and other neurons, we also used the primary culture to compare midbrain dopamine neurons with hippocampal glutamate neurons, and found that α-synuclein inhibits transmitter release in both populations.

In collaboration with our lab neighbor Roger Nicoll, we found that hippocampal slices prepared acutely from transgenic mice also show a reduction in transmitter release, establishing the physiological relevance of our findings in culture. Further, we used the culture system to show that the effect on release requires the N-terminal membrane-binding domain of α-synuclein.

The paper by Roy and colleagues also shows that α-synuclein inhibits transmitter release. The effect on synaptic vesicle exocytosis appears different from what we observed, and they also find a variety of other changes that we did not. We observed no effect of α-synuclein on the rate of synaptic vesicle exocytosis; the Roy paper uses FM dyes to suggest an effect on the rate but does not corroborate this with other methods. Surprisingly, Roy et al. use transgenic mice to produce the cultures that serve as the basis for their experiments, but perform little analysis using the mice themselves to corroborate their in-vitro findings in vivo. Rather, they rely on the cultures to pursue biochemical and ultrastructural analysis, finding 1) a major reduction in all synaptic vesicle proteins, including some synaptic boutons without synaptic vesicle proteins that they term “vacant boutons,” although it is a bit difficult to call anything a bouton if there are no synaptic vesicles in it; and 2) gross changes in presynaptic ultrastructure by EM.

It is true that culture can be very helpful to elucidate changes at the level of individual boutons. Yet our transgenic mice express α-synuclein in essentially all neurons, so we should also have seen a reduction in synaptic vesicle proteins if there were any. Furthermore, we did observe a reduction in the synapsins, but not other synaptic vesicle proteins, demonstrating that we could detect a biochemical effect of the transgene. We also looked at the transgenic mice by electron microscopy and found a much more specific effect of α-synuclein overexpression—a dispersion of synaptic vesicles away from the release site.

Overall, the Roy paper attributes the effect of α-synuclein on synaptic transmission to “upstream events,” but also states that the effects are pleiotropic and hence suggestive of toxicity. In contrast, we found very selective effects on the transmitter release mechanism and little evidence of toxicity. So the debate comes down to a basic question: Does α-synuclein overexpression produce changes through a gain in the normal function of the protein (as we suggest) or through the gain of an abnormal function (as suggested by Roy et al.)? This is a profound question with direct relevance for the pathogenesis of PD. It is always difficult to tell whether the toxicity observed is relevant to the disease, or just some other kind of injury. That is why we prefer to study a system with selective rather than general effects.

In the end, the question of normal function will be settled through the analysis of α-synuclein knockout mice. At this point, only double-knockout mice have been reported, but triple-knockouts lacking all the isoforms exist and are now being analyzed. If these animals show an increase in transmitter release, it would strongly suggest that the effects we observe involve a gain in the normal function of α-synuclein. Indeed, recent work using double-knockout mice has suggested an increase in dopamine release (Senior et al. 2008). Speaking in more practical terms, it will be difficult to elucidate the toxicity observed by Roy et al. since it is not clear where to begin. In contrast, we think that the selectivity of the defect we observe provides a clear starting point for future investigation.

In summary, both our and Roy's studies observe an effect of α-synuclein on synaptic vesicle exocytosis, but the details and the interpretation are quite different. The extent of our analysis in multiple experimental systems with a range of complementary methods suggests that the effect of α-synuclein is highly specific, and perhaps related to its normal role. However, this conclusion awaits further analysis of α-synuclein knockout mice, and identification of the mechanism by which α-synuclein acts to inhibit synaptic vesicle exocytosis. The identification of a specific effect also provides an entry point for future study of its role in disease as well as normal physiology.

View all comments by Robert Edwards

The work by Scott and colleagues is of great interest as it is trying to pinpoint the molecular details in the synaptic pathology caused by a modest transgenic overexpression of α-synuclein. The authors found that PK-resistant and abnormally phosphorylated α-synuclein tends to accumulate in dysfunctional boutons. They also elegantly demonstrated that such boutons display a gradual reduction in levels of certain endogenous presynaptic proteins. In an attempt to extend their findings to human disease, they looked for and confirmed similar alterations on a DLB brain section.

I think another transgenic model that moderately overexpresses another neuronal protein (e.g., APP) should have been looked at in parallel (to exclude that the effects seen are merely an effect of protein overproduction). Also, more human cases should have been included to verify that the observed differences are truly relevant to disease. Even so, the findings are intriguing, and the described model would be very useful to test effects of heat-shock proteins and other putative rescuing molecules. Moreover,...  Read more

The work by Scott and colleagues is of great interest as it is trying to pinpoint the molecular details in the synaptic pathology caused by a modest transgenic overexpression of α-synuclein. The authors found that PK-resistant and abnormally phosphorylated α-synuclein tends to accumulate in dysfunctional boutons. They also elegantly demonstrated that such boutons display a gradual reduction in levels of certain endogenous presynaptic proteins. In an attempt to extend their findings to human disease, they looked for and confirmed similar alterations on a DLB brain section.

I think another transgenic model that moderately overexpresses another neuronal protein (e.g., APP) should have been looked at in parallel (to exclude that the effects seen are merely an effect of protein overproduction). Also, more human cases should have been included to verify that the observed differences are truly relevant to disease. Even so, the findings are intriguing, and the described model would be very useful to test effects of heat-shock proteins and other putative rescuing molecules. Moreover, with the emergence of novel antibodies and other detection tools, it will be interesting to relate cellular effects and the distribution of monomeric, oligomeric, and fibrillar α-synuclein accumulating presynaptically and in other parts of the affected neuron.

Effects on neurotransmission by α-synuclein were the subject of study in the paper by Nemani et al. Also here, a modest increase in the intraneuronal levels of α-synuclein was sufficient to cause aberration. More specifically, the N-terminal domain of α-synuclein seems to be critical in mediating an impairment in transmitter release. However, contrary to the study by Roy, this paper did not find any corresponding changes in vesicle numbers or presence of presynaptic proteins (although the experimental set-up was different and the two groups did not study the same proteins).

Taken together, the two studies demonstrate new and interesting aspects of synaptic pathology induced by deposition of pathological α-synuclein. Applying the insights from the study by Nemani et al. on the model presented by Scott et al., it would be of interest to see if the N-terminal part of α-synuclein is responsible for all the aspects described.

View all comments by Martin Ingelsson

Both papers present evidence that the pathophysiological mechanism in synucleinopathies is not neuronal cell death but a synaptic dysfunction; that is very interesting. With regard to the clinical symptoms in PD, (also PDD and DLB), the synaptic pathology is due to a decrease in neurotransmitter release. The two publications provide us with a link between α-synuclein overexpression and an impairment of vesicle turnover. With this approach, it might be possible to explain the clinical symptoms of PD. Both papers show that α-synuclein-related pathology is not restricted to dopaminergic neurons.

The conclusion to be drawn from the results of these papers is that PD and DLB research should move away from models of α-synuclein-related toxicity or cell death that can be achieved only by unphysiologically high overexpression of α-synuclein. Rather, research should concentrate on synaptic failure associated with moderately altered α-synuclein levels. The link to α-synuclein aggregation was only drawn in the Scott et al. paper.

View all comments by Walter J. Schulz-Schaeffer

α-synuclein and Synaptic Failure in PD
α-synuclein has been biochemically and genetically linked to sporadic and familial PD. Mutations or multiplications of the α-synuclein gene cause familial forms of PD (Polymeropoulos et al., 1997; Krüger et al., 1998; Singleton et al., 2003; Zarranz et al., 2004). The aberrant function of α-synuclein is not understood, although there is evidence that abnormal folding and aggregation may play a role and that the toxic α-synuclein species may be oligomeric intermediates. It has been shown that α-synuclein is highly enriched in presynaptic terminals. At this site, it could be acting as a modifier of synaptic vesicle recycling, dopamine storage, and release at nerve terminals. Recent work has also suggested a role for α-synuclein in SNARE-mediated exocytosis at the synapse. In this respect, the synaptic role of α-synuclein is based primarily on the...  Read more

α-synuclein and Synaptic Failure in PD
α-synuclein has been biochemically and genetically linked to sporadic and familial PD. Mutations or multiplications of the α-synuclein gene cause familial forms of PD (Polymeropoulos et al., 1997; Krüger et al., 1998; Singleton et al., 2003; Zarranz et al., 2004). The aberrant function of α-synuclein is not understood, although there is evidence that abnormal folding and aggregation may play a role and that the toxic α-synuclein species may be oligomeric intermediates. It has been shown that α-synuclein is highly enriched in presynaptic terminals. At this site, it could be acting as a modifier of synaptic vesicle recycling, dopamine storage, and release at nerve terminals. Recent work has also suggested a role for α-synuclein in SNARE-mediated exocytosis at the synapse. In this respect, the synaptic role of α-synuclein is based primarily on the results of knockout studies (Chandra et al., 2005; Larsen et al., 2006). Still, the effects of α-synuclein overexpression on synaptic function had not received much attention. The recent papers by Nemani et al., 2010, and Scott et al., 2010, clearly show that overexpression of full-length α-synuclein at mild levels leads to defects in the synapse, including altered exocytosis, suggesting that this is an early event in the pathogenesis of PD.

In the Nemani et al. study, the authors use a battery of elegant optical and physiological in vitro and in vivo experiments to show, for the first time, that a relatively short time of overexpression of α-synuclein leads to the fast appearance of presynaptic defects in glutamatergic hippocampal neurons and mesencephalic dopaminergic neurons.

What is exciting about this manuscript is that the reduction of neurotransmitter release occurs under only modest overexpression of α-synuclein and in the absence of any aggregation and toxicity. What is more, the effects appear to be dose-dependent. This suggests that the observed effects might reflect early pathologic events in the disease pathway. Detailed kinetic examination further demonstrated that the inhibition did not involve defects in vesicle fusion or a reduction in the number of transmitter-containing vesicles, but rather a specific defect in the synaptic vesicle recycling pathway by preventing the reclustering of vesicles after endocytosis. Interestingly, the effect was specific to membrane-associated mutations of α-synuclein and therefore to the N-terminus of the molecule.

Although the molecular pathway by which overexpression of α-synuclein inhibits synaptic vesicle reclustering was not deciphered in the study of Nemani et al., it is possible that synapsin downregulation observed in α-synuclein overexpressing cells may play a role. Still, a direct physical (inter)action of the proteins was not identified.

To address the question of α-synuclein expression and synapse physiology, and to understand the mechanisms by which α-synuclein expression affects synapse function, Scott et al. set out a series of rigorous quantitative cell biological experiments using a transgenic mouse model in which human α-synuclein was tagged at the C-terminus to GFP (Rockenstein et al., 2005). Unlike the study by Nemani et al., the model of α-synuclein overexpression used by Scott et al. exhibited post-translationally modified and pathologically altered α-synuclein despite the modest levels of expression. Using electrophysiological assessment, the authors elegantly demonstrated a significant reduction in neurotransmitter release and a failure of the presynaptic exocytotic machinery in the synaptic boutons of transgenic mice neurons. Importantly, styryl dye uptake experiments further suggested that the recycling machinery in the transgenic cultures was inoperable, since a significant number of boutons overexpressing α-synuclein had failed to endocytose the dye. Electron microscopy examination of such synapses further revealed variation in the size of synaptic vesicles, including vesicles enlarged in size. Since this phenotype resembled previously reported animal models that lacked presynaptic proteins (Schoch et al., 2001; Nonet et al., 1998; Deitcher et al., 1998), the authors went on to quantitatively evaluate the levels of a number of endocytic and exocytic proteins (including synapsin) in transgenic synapses and found that they were either absent or diminished.

The authors concluded (and rightly so), that multiple exocytic and endocytic pathways are involved in α-synuclein pathogenesis. Significantly, such changes were also observed in human autopsy samples of synucleinopathies (DLB). In this respect, it would have been interesting to see whether and how the distribution of such proteins changes in the vulnerable brain areas during aging. What is important in this study of Scott et al. is the sustained expression of α-synuclein in the model used, and the observation that the protein is pathologically altered. It is very likely that misfolded and/or aggregated α-synuclein have different effects on the synaptic function and morphology. One might also conclude that a long-lasting expression of α-synuclein, as in the case of multiplications of the gene, has different effects on the physiology and morphology of the synapse, to a transient/shorter one as the two studies suggest. Again, the identification of species generated in the two scenarios is in need of further examination.

Another question that arises is whether “aggregated” α-synuclein species have a direct interaction with presynaptic proteins. What would the effect of “oligomeric” modifiers be on the morphology of the vesicles and function of the synapse? Collectively, the findings presented in these studies suggest that PD may result from a “dying back” process. This would be an early event initiated at the site of synapse, stemming from the accumulation and misfolding of α-synuclein and leading to degeneration of basal ganglia axons followed by more widespread denervation. However, it will take many more studies to pinpoint which of the cellular actions of overexpressed α-synuclein lie at the center of synaptic physiology. A critical question that remains open is how a reduction in neurotransmitter release as an initiating event can lead to inclusions pathology and neuronal demise. An answer to this question may provide insights regarding the early steps that lead to neurodegeneration, and that could further identify targets for preventative intervention. For example, development of drugs that inhibit α-synuclein actions at the synapse could be a potentially effective treatment for Parkinson disease.

View all comments by Kostas Vekrellis