The protein α-synuclein has a central role in the pathogenesis of Parkinson's disease. Like that of other proteins that accumulate in neurodegenerative disease, however, the function of α-synuclein remains unknown. Localization to the nerve terminal suggests a role in neurotransmitter release, and overexpression inhibits regulated exocytosis, but previous work has failed to identify a clear physiological defect in mice lacking all three synuclein isoforms. Using adrenal chromaffin cells and neurons, we now find that both overexpressed and endogenous synuclein accelerate the kinetics of individual exocytotic events, promoting cargo discharge and reducing pore closure ('kiss-and-run'). Thus, synuclein exerts dose-dependent effects on dilation of the exocytotic fusion pore. Remarkably, mutations that cause Parkinson's disease abrogate this property of α-synuclein without impairing its ability to inhibit exocytosis when overexpressed, indicating a selective defect in normal function.
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We thank members of the Edwards laboratory for discussion, D. Jullié for help with the pH oscillation experiment, A. Bertholet (UCSF) for the TOM20 antibody and B. Calagui and S. Batarni for technical assistance. We also thank K. Bohannon, M. Bittner and R. Holz for sharing data and providing suggestions. This work was supported by grants from NINDS (NS062715), NIDA (DA10154) and the Weill Institute for Neurosciences (to R.H.E.), the John and Helen Cahill Family Endowment for Research on Parkinson's Disease (to R.H.E.), a fellowship from NINDS (to T.L.) and a fellowship from the A.P. Giannini Foundation (to J.B.).
The authors declare no competing financial interests.
Integrated supplementary information
Supplementary Figure 1 Endogenous and lentiviral expression of α-synuclein in adrenal chromaffin cells.
(a) Chromaffin cells from wild type (wt) or synuclein triple knockout (TKO) mice were transduced with either lentivirus encoding human α-synuclein (SYN) or empty vector, cultured for 72 h and immunostained for the over-expressed protein using the human-specific α-synuclein antibody 15G7 (left) as well as the dense core vesicle protein secretogranin II (SgII) to identify chromaffin cells (right).(b) Chromaffin cells from wt and synuclein TKO mice were immunostained using the α-synuclein-specific antibody syn-1, which detects both rodent and human isoforms. Comparison to the TKO shows that wt cells express low levels of endogenous α-synuclein in a diffuse cytosolic distribution. Scale bar, 5 μm. (c) Quantification of whole cell α-synuclein immunofluorescence detected with syn-1 antibody in (b) indicates ~5-fold overexpression after lentiviral infection. Values indicate mean ± SEM, n = 10 cells for each group. a.u., arbitrary units
(a) Chromaffin cells from wild type and synuclein TKO mice were transduced with lentivirus encoding wild type human α-synuclein (SYN) or empty vector (wt and TKO) 3-5 days before imaging, incubated in Fluo-5F AM (6 μM) for 15 min and imaged by TIRF microscopy during the addition of 45 mM K+. Values represent mean ± SEM. (b) Peak Fluo-5F fluorescence observed during stimulation is unaffected by synuclein (p = 0.4571 by one-way ANOVA; F(2, 32) = 0.8023). wt, n = 13 cells; SYN, n = 12 cells; TKO, n = 10 cells from two independent cultures.
(a) Representative dual color imaging traces of BDNF-pHluorin exocytotic events with fast (left) and slow (right) rise times. The loss of FFN206 fluorescence indicates that slow as well as fast rise times can reflect exocytosis, and the lag between onset of FFN loss and onset of BDNF-pHluorin unquenching for the slow event illustrates the effect of the fusion pore on behavior of the two reporters. 30/35 pHluorin events with rise time >150 ms and 32/48 with a shorter rise time exhibit an associated FFN release event. The high proportion (~30%) of new arrivals with extremely short duration (in many cases <10 ms) (data not shown) makes it impossible to detect all FFN release events with the alternating 30 ms illumination required for dual imaging of the two fluorophores. Size bar indicates 1 μm.(b) Scatterplot of the time constant for FFN206 loss as a function of BDNF-pHluorin rise time. Linear regression demonstrates a correlation (R2 = 0.12, p = 0.008), accounting for the higher proportion of fast pHluorin events with undetectable FFN release. n = 83 events from 2 cells (c) Representative traces of a decaying chromaffin cell BDNF-pHluorin event quenched by low pH buffer (MES) (left), a stable event quenched by MES (center), and a stable event protected from quenching by MES (right). afu, arbitrary fluorescence units (d) All events in the process of decay were quenched by low pH MES buffer, eliminating the possibility that decay of BDNF-pHluorin fluorescence results from vesicle movement out of the TIRF plane. For stable events, MES application did not always result in quenching, indicating that the fusion pore can limit BDNF-pHluorin release but retain continuity with the external solution. In addition, only stable events have the potential for complete pore closure. (e) Experiments performed in the absence and presence of bafilomycin (0.6 μM) showed no difference in the kinetics of BDNF-pHluorin fluorescence decay, excluding a role for vesicle reacidification in the rate of release. wt, n = 213 / 124 events; SYN, n = 117 / 60 events; TKO, n = 178 / 190 events (+ / - bafilomycin)
(a) Time course of a single exocytotic event with slow rise time and interrupted release. a.u., arbitrary units (b) The time to 90% peak BDNF-pHluorin fluorescence was determined as in Figure 1b, and represented here for wild type, α-synuclein overexpression and synuclein TKO as mean ± SEM (****, p < 0.0001 by Kruskal-Wallis one-way ANOVA; H = 84.20). (c) The mean time to peak per cell plotted as a function of event number per cell shows that single cells do not distort the analysis of individual exocytotic events. (d) The peak fluorescence was normalized and the mean time course of fluorescence decay determined for all exocytotic events on a per cell basis. For all comparisons, p < 0.0001 by one-way ANOVA with Tukey’s multiple comparisons test (F(2, 842) = 181.0). n = 19 cells per group (c,d) (e) Representative kymographs depicting the BDNF-pHluorin event classes presented in Figure 1. (f) Cumulative frequency distribution of the data shown in Figure 1d.
Supplementary Figure 5 Synuclein expression does not affect the number of docked chromaffin granules or their intravesicular pH.
Chromaffin cells from wt or TKO mice were transduced with lentivirus encoding BDNF-pHluorin, cultured for 5 days and imaged by TIRF microscopy. BDNF-pHluorin-expressing LDCVs were identified using 50 mM NH4Cl to alkalinize acidic compartments, the fluorescent punctae subjected to automated filtering and analyzed in ImageJ. (a) Synuclein loss (TKO) or over-expression (SYN) do not affect the number of docked vesicles per cell. (b) Synuclein expression does not affect lumenal pH. The fold change in fluorescence due to 50 mM NH4Cl was determined for individual LDCVs and the averages per cell plotted along with mean ± SEM. n.s., not significant by one-way ANOVA (p = 0.806 for (a) (F(2, 30) = 0.2173) and p = 0.772 for (b) (F(2, 30) = 0.261)); wt, n = 12 cells, 162 vesicles; TKO, n = 11 cells, 154 vesicles; SYN, n = 10 cells, 151 vesicles
(a) Overexpression of α-syn (SYN) reduces the frequency of BDNF-pHluorin exocytotic events (****, p < 0.0001 by one-way ANOVA with Tukey’s post hoc comparison; F(2, 52) = 10.98). wt, n = 16 cells; SYN, n = 18 cells; TKO, n = 21 cells from three independent cultures (b) As described in figure S4, the release of BDNF-pHluorin was determined across all events by normalizing the peak fluorescence and presenting the mean loss of fluorescent cargo per cell. p < 0.0001 for all comparisons by one-way ANOVA with Tukey’s post hoc comparison (F(2, 253) = 65.65). wt, n = 11 cells; SYN, n = 9 cells; TKO, n = 11 cells (c) BDNF-pHluorin event classes (defined in Figure 1C) showed a similar distribution to events recorded at 5 mM Ca++. Synuclein overexpression reduced the fraction of events with pore closure relative to the synuclein TKO (***, p < 0.001 by one-way ANOVA with Tukey’s post hoc comparison (F(2, 28) = 5.334; q = 4.602, TKO vs SYN)). n = 11 (wt), 9 (SYN) and 11 (TKO)(d) Overexpression of α-synuclein reduces and loss of all synucleins increases the time constant of BDNF-pHluorin fluorescence decay. For all events that decayed completely to baseline fluorescence values, the time constants of decay were determined by fitting single exponentials to the decay component of the trace. The distributions differ with p < 0.01 for wt-SYN comparison, p < 0.05 for wt-TKO and p < 0.001 for SYN-TKO (Kolmogorov-Smirnov). **, p < 0.01; ***, p < 0.001; ****, p < 0.0001 by Kruskal-Wallis one-way ANOVA with Dunn’s post hoc test (H = 43.76). wt, n = 213 events; SYN, n = 117 events; TKO, n = 178 events
The mean kinetic parameters for each cell (obtained from Fig. 2) are plotted as a function of event number. The effects of over-expressed wild type human α-synuclein on latency to decay (a) and time constant of decay (b) do not reflect the distribution of event numbers per cell. Data points represent individual cells.
Primary, dissociated rat hippocampal neurons were co-electroporated with BDNF-pHluorin, synaptophysin-mCherry and either α-synuclein or empty vector as described in Figure 3. After 14 days in vitro, the neurons were harvested, and α-synuclein levels from four independent cultures (1-4) quantified by fluorescent western analysis (a). (b) α-Synuclein immunoreactivity was normalized to that of actin and expressed as fold-overexpression relative to cells transfected with empty vector. mean ± SEM, 4.6 ± 0.5
Wild type (wt) and synuclein TKO hippocampal neurons were transfected with BDNF-pHluorin and imaged 14-20 days later, stimulating at 50 Hz for 5 s followed by transient quenching of the cell surface fluorescence at pH 5.5 as in Figure 3a-d. (a,b) Loss of synuclein has no effect on the frequency of exocytotic events per coverslip (p = 0.436 by unpaired t-test; t(17) = 0.798) (a) or the proportion of slowly decaying events in each coverslip quenchable with acidic buffer (p = 0.258 by unpaired t-test; t(17) = 1.170) (b). Data indicate mean ± SEM. (c) Events were classified as already decayed at the time of acid application or for those that were not, either quenched or unquenched by the low pH (p = 0.16 by Chi-square test). n = 397 events from three cultures for both wt (11 coverslips) and TKO (8 coverslips).
(a) Wild type mouse hippocampal neurons transfected with NPY-pHluorin were stimulated at 50 Hz for 5 s in the absence (con) or presence of bafilomycin (0.6 μM, +BafA). Individual traces were fit to a plateau followed by single exponential decay. Events that failed to show fluorescence decay were scored as no decay, and those that did show decay were classified as fast if τ < 5 s or slow if τ > 5 s (p < 0.01 by Chi-square test). n=198 events / 3 coverslips for both conditions. (b) Cumulative frequency distribution of τdecay values, including events that did not decay. p = 0.25 by Kolmogorov-Smirnov.
The mean kinetic parameters for each coverslip are plotted as a function of event number, using the data shown in Figure 4. The effects of wild type human α-synuclein over-expression on latency to decay (a) and time constant of decay (b) do not reflect event number. Similarly, the effects of the synuclein TKO on latency to decay (c) and time constant of decay (d) do not vary systematically with event number per coverslip.
(a,b) NPY-pHluorin events from rat hippocampal neurons over-expressing human α-synuclein (syn) and controls were separated into those with time constants of fluorescent decay more than 5 s (a) and less than 1 s (b), and the latency to decay plotted by cumulative frequency (p = 0.97 for a and < 0.0001 for b by Kolmogorov-Smirnov). n(a) = 65 events / 5 coverslips for control and 23 events / 8 coverslips for syn; n(b) = 197 events for control and 210 for syn (c,d) NPY-pHluorin events from the hippocampal neurons of wt and TKO mice were separated into similar groups as in (a) and (b) and displayed by cumulative frequency. Synuclein affects the latency to decay only for more rapidly decaying events (p = 0.054 for c and < 0.0001 for d by Kolmogorov-Smirnov). n(c) = 99 events / 10 coverslips for wt and 185 events / 11 coverslips for TKO; n(d) = 750 events for wt and 474 events for TKO. Insets indicate mean values ± SEM. n.s., not significant (p = 0.853 for a and 0.0753 for c); ****, p < 0.0001 by Mann-Whitney; U = 727.5 (a), 13982 (b), 7984 (c) and 121060 (d)
Supplementary Figure 13 Endogenous synuclein concentrates at presynaptic terminals in cultured neurons.
Primary hippocampal neurons from wt or synuclein TKO mice were cultured for 18 days, fixed, immunostained for α/β-synuclein using the H3C antibody (green), and for the vesicular glutamate transporter 1 (VGLUT1, red) and imaged by confocal microscopy. Size bar, 5 μm.
Supplementary Figure 14 Synuclein does not colocalize with mitochondria in adrenal chromaffin cells.
Chromaffin cells from wt mice transduced with lentivirus encoding human α-synuclein were immunostained for synuclein using the H3C antibody and for mitochondria using an antibody to the outer membrane protein TOM20. The images were obtained by structured illumination and are shown here as reconstructions of a 120 nm-thick slice located within 0.5 μm of the cell-coverglass interface. Size bar, 2.5 μm.
Supplementary Figure 15 Mutations associated with Parkinson’s disease do not perturb the localization of human α-synuclein to LDCVs in synuclein TKO mice.
Chromaffin cells from synuclein TKO mice were isolated, transduced with either empty vector or lentivirus encoding one of PD-associated α-synuclein mutants and immunostained 5 days later for α-synuclein (H3C, green) as well as the dense core vesicle protein secretogranin II (SgII, red). Representative TIRF images show that both mutants localize to secretory vesicles even in the absence of endogenous synuclein. Size bar, 2.5 μm.
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Logan, T., Bendor, J., Toupin, C. et al. α-Synuclein promotes dilation of the exocytotic fusion pore. Nat Neurosci 20, 681–689 (2017) doi:10.1038/nn.4529
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