Fig. 4: Relationship between α-synuclein enrichment in dopaminergic terminals and dopaminergic synaptic loss.

A Syn1 α-synuclein, B pSer129 α-synuclein, and C CTT122 α-synuclein enrichment in DAT synapses is associated with DAT loss in the putamen across all cases. The top row shows a representative 3D surface-rendering image of DAT synapses (magenta) positive for α-synuclein proteoforms (green) (scale bar 0.5 µm). The middle row shows the correlation of A the density of Syn1 α-synuclein+ DAT synapses and DAT synaptic loss (data points are average per case across all 6 ROIs and colour-coded for Braak α-synuclein stage), B the percentage of DAT synapses positive for pSer129, and C CTT122 α-synuclein and DAT loss (data points are average per case across all 6 ROIs and colour-coded for group; black: regression line for all cases; red: regression line for iLBD cases; blue: regression line for PD cases; the grey area around the regression line represents the standard error). The bottom row shows the same correlation across Braak α-synuclein stages, where the grey line shows the mean DAT synaptic density (right y axis) and the magenta line the mean α-synuclein proteoform⁺ DAT synaptic density/percentage (left y axis) per Braak α-synuclein stage (x axis). The statistical test used is a two-sided Spearman’s correlation with age and sex as covariates. Multiple testing comparison corrections were performed with the Tukey test. Exact p values: A: all cases rho = 0.61, p < 0.001; B: all cases rho = −0.54, p < 0.001; iLBD rho = −0.51, p = 0.002; PD p = 0.905; C: all cases rho = −0.47, p < 0.001; iLBD rho = −0.31, p < 0.001; PD p = 0.493. Source data are provided as a Source Data file. α-syn α-synuclein, DAT dopaminergic transporter, iLBD incidental Lewy body disease, PD Parkinson’s disease, PSD95 post-synaptic density 95, VGLUT1 vesicular glutamatergic transporter 1. 0.10 < p ≤ 0.05^#, p < 0.05^*, p < 0.01^**, p < 0.001^***.