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All data necessary for the conclusions of the study are available in ‘Main’, Figs. 1–6 and Extended Data Figs. 1–10. Source data are provided with this paper.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (82271447 and 81771382 to Z.Z. and 82301430 to X.Y.), the National Key Research and Development Program of China (2019YFE0115900 to Z.Z.), the Innovative Research Groups of Hubei Province (2022CFA026 to Z.Z.) and the Natural Science Foundation of Hubei Province (2021CFB451 to S.N.).
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Extended data
Extended Data Fig. 1 α-Syn pathology in the kidneys, CNS and gastrointestinal tract of patients with PD and CKD.
a, Quantification of immunohistochemistry in Fig. 1a showing the positive pα-Syn area in the kidneys of patients with PD (n = 7 samples per group; P = 0.0057). b, Immunohistochemistry of Syn303 antibody in the kidneys of patients with PD (arrowheads: pα-Syn-positive signals; n = 6 samples per group; P = 0.0004). c, Immunohistochemistry of pα-Syn in the cortex of α-Syn A53T mice and Snca−/− mice. d, Immunohistochemistry of pα-Syn in the stomach (i), small intestine (ii) and large intestine (iii) of patients with PD (arrowheads: pα-Syn-positive signals; n = 6 samples per group; P = 0.0012 (left), P = 0.0003 (middle), P < 0.0001 (right)). e, Immunohistochemistry of Syn303 antibody in the kidneys of patients with CKD and control subjects (i–vii: CKD, viii: control, arrowheads: pα-Syn-positive signals; n = 6 samples per group; P = 0.0007). f, Double immunofluorescence of CD31 and pα-Syn in the kidneys of patients with CKD and control subjects (arrowheads: pα-Syn-positive signals; n = 6 samples per group; P < 0.0001). g, Immunohistochemistry of the Syn303 antibody in the spinal cord (i, ii), amygdala (iii, iv) and midbrain (v, vi) of patients with CKD (arrowheads: pα-Syn-positive signals). h, Thioflavin T (ThT) analysis showing the fibrillization of α-Syn in the presence of kidney tissues from patients with PD or CKD and control subjects. Error bars indicate the mean ± s.e.m. **P < 0.01, ***P < 0.001. Unpaired two-tailed Student’s t-test was used. AU, arbitrary units; AFU, arbitrary fluorescence units. Scale bars: 20 μm (b,f) and 50 μm (c,d,e,g).
Extended Data Fig. 2 The kidneys physiologically remove α-Syn from the blood.
a,b, Mice with normal kidney (a) or renal failure (b) were intravenously injected with recombinant human α-Syn PFFs. The concentrations of human α-Syn in the serum and urine were determined at different times after injection. c, Total α-Syn in the 24-hour urine of mice injected with α-Syn or PFFs (c) (n = 5 mice per group, P < 0.0001 (control PBS vs. control α-Syn, renal failure PBS vs. renal failure α-Syn), P = 0.5176 (control α-Syn vs. renal failure α-Syn), error bars indicate the mean ± s.e.m; ns, not significant; ***P < 0.001, two-way ANOVA). d, Immunohistochemistry showing the overall distribution of human α-Syn in the kidney at 30 min after intravenous injection of human α-Syn monomers. e, Immunohistochemistry of human α-Syn in different organs of mice without renal failure at different time points after intravenous injection of recombinant human α-Syn monomers. f, Immunohistochemistry of human α-Syn in different organs of mice with renal failure at different time points after intravenous injection of recombinant human α-Syn monomers. Scale bars: 100 μm (d) and 20 μm (e,f).
Extended Data Fig. 3 Validation of α-Syn PFFs and evaluation of the renal function of mice with renal failure.
a, Endotoxin levels of recombinant α-Syn before and after removal of endotoxin (n = 5 independent experiments; P < 0.0001). b, Transmission electron microscopy (TEM) analysis of human and mouse α-Syn preformed fibrils (PFFs) before and after sonication. c, ThT analysis showing the fibrillization of α-Syn PFFs used in the experiments. d, LDH release of the primary cortical neurons incubated with human or mouse α-Syn PFFs (n = 5 independent experiments; P < 0.0001). e, H&E staining of the kidneys. f,g, PAS staining (f) and quantification (g) of the kidneys. h, The serum creatinine (SCr) levels of mice with or without renal failure (n = 12 mice per group; P < 0.0001). i, The blood urea nitrogen (BUN) levels of mice with or without renal failure (n = 12 mice per group; P < 0.0001). j, The blood cystatin C levels of mice with or without renal failure (n = 12 mice per group; P < 0.0001). k, Double immunofluorescence of CD31 and pα-Syn in the kidneys of control mice or mice with renal failure that were injected with α-Syn monomers or PFFs (arrowheads: CD31-positive signals (green) and pα-Syn-positive signals (magenta)). Error bars indicate the mean ± s.e.m. ***P < 0.001. Unpaired two-tailed Student’s t-test was used. Scale bar: 200 nm (b) and 20 μm (e,f,k).
Extended Data Fig. 4 Renal failure exacerbates α-Syn pathology induced by intravenous injection of α-Syn PFFs.
a, Quantification of immunohistochemistry in Fig. 3b showing the levels of pα-Syn in the glomeruli, renal medulla, spinal cord, substantia nigra (SN), basolateral amygdala (BLA), hippocampus (HIP), striatum (STR) and cortex (CTX) of control mice or mice with renal failure that were injected with α-Syn monomers or PFFs (n = 5 mice per group; P = 0.0255 (glomeruli, monomers vs. RF + monomers), P = 0.0193 (glomeruli, monomers vs. PFFs), P = 0.0001 (glomeruli, RF + monomers vs. RF + PFFs), P = 0.0002 (glomeruli, PFFs vs. RF + PFFs), P = 0.0028 (spinal cord, monomers vs. RF + monomers), P = 0.0042 (spinal cord, monomers vs. PFFs), P = 0.0007 (spinal cord, RF + monomers vs. RF + PFFs), P = 0.0005 (spinal cord, PFFs vs. RF + PFFs), P = 0.0001 (SN, RF + monomers vs. RF + PFFs), P = 0.0002 (SN, PFFs vs. RF + PFFs), P = 0.0267 (STR, monomers vs. PFFs), P = 0.0003 (STR, PFFs vs. RF + PFFs), P = 0.0007 (CTX, monomers vs. RF + monomers), P = 0.0002 (CTX, monomers vs. PFFs), P = 0.0002 (CTX, PFFs vs. RF + PFFs), P < 0.0001 (glomeruli: monomers vs. RF + PFFs, renal medulla, spinal cord: monomers vs. RF + PFFs, SN: monomers vs. RF + PFFs, BLA, HIP, STR: monomers vs. RF + PFFs, CTX: monomers vs. RF + PFFs, RF + monomers vs. RF + PFFs)). b, Heatmap showing the propagation of α-Syn inclusions in the brains of control mice or mice with renal failure that were injected with α-Syn monomers or PFFs. The image represents the average pathology of 5 mice per group. c,d, Western blot analysis of the pα-Syn antibody in the ventral midbrain of control mice or mice with renal failure that were injected with α-Syn monomers or PFFs (n = 5 mice per group; P < 0.0001). e, HPLC analysis of DA, DOPAC and HVA in the striatum of control mice or mice with renal failure that were injected with α-Syn monomers or PFFs (n = 5 mice per group; P = 0.0327 (DA), P = 0.0197 (DOPAC), P = 0.0452 (HVA)). f–h, Behavioral test results. Pole test (f), beam-walking test (g) and footprint test (h) (n = 12 mice per group; P = 0.0257 (f, left), P = 0.0263 (f, right), P = 0.0152 (g, RF + monomers vs. RF + PFFs), P < 0.0001 (g, monomers vs. RF + PFFs), P = 0.0001 (g, PFFs vs. RF + PFFs), P = 0.1122 (h, left, monomers vs. RF + PFFs), P = 0.3859 (h, left, RF + monomers vs. RF + PFFs), P = 0.0729 (h, left, PFFs vs. RF + PFFs), P = 0.1035 (h, right, monomers vs. RF + PFFs), P = 0.9640 (h, right, RF + monomers vs. RF + PFFs), P = 0.5515 (h, right, PFFs vs. RF + PFFs)). Error bars indicate the mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001. For a, b, f, g and h, one-way ANOVA was used. For e, the Kruskal–Wallis test was used. AU, arbitrary units.
Extended Data Fig. 5 Subtotal nephrectomy exacerbates α-Syn pathology.
a, Timeline of the experiments. b,c, Immunohistochemistry of pα-Syn in the glomeruli, spinal cord, substantia nigra (SN), basolateral amygdala (BLA), hippocampus (HIP), striatum (STR) and cortex (CTX) of control mice or mice with subtotal nephrectomy that were injected with α-Syn monomers or PFFs (P = 0.0001 (glomeruli, monomers vs. PFFs), P = 0.0096 (glomeruli, subtotal nephrectomy + monomers vs. PFFs), P = 0.0083 (renal medulla, monomers vs. PFFs), P = 0.0338 (renal medulla, subtotal nephrectomy + monomers vs. PFFs), P = 0.0190 (spinal cord, monomers vs. subtotal nephrectomy + monomers), P = 0.0011 (spinal cord, monomers vs. PFFs), P = 0.0237 (CTX, monomers vs. subtotal nephrectomy + monomers), P = 0.0084 (CTX, monomers vs. PFFs), P = 0.0001 (CTX, PFFs vs. subtotal nephrectomy + PFFs), P < 0.0001 (glomeruli: monomers vs. subtotal nephrectomy + PFFs, subtotal nephrectomy + monomers vs. subtotal nephrectomy + PFFs, PFFs vs. subtotal nephrectomy + PFFs, renal medulla: monomers vs. subtotal nephrectomy + PFFs, subtotal nephrectomy + monomers vs. subtotal nephrectomy + PFFs, PFFs vs. subtotal nephrectomy + PFFs, spinal cord: monomers vs. subtotal nephrectomy + PFFs, subtotal nephrectomy + monomers vs. subtotal nephrectomy + PFFs, PFFs vs. subtotal nephrectomy + PFFs, SN, BLA, HIP, STR, CTX: monomers vs. subtotal nephrectomy + PFFs, subtotal nephrectomy + monomers vs. subtotal nephrectomy + PFFs)). d, Western blot analysis of pα-Syn in the brain cortex of control mice or mice with subtotal nephrectomy that were injected with α-Syn monomers or PFFs (P < 0.0001). Error bars indicate the mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001. n = 5 mice per group, one-way ANOVA was used. Scale bars: 20 μm.
Extended Data Fig. 6 Renal failure promotes α-Syn pathology in α-Syn A53T mice.
a, Timeline of the experiments. b, Quantification of immunohistochemistry in Fig. 4a showing the levels of pα-Syn in the spinal cord, substantia nigra compacta (SNc), basolateral amygdala (BLA), hippocampus (HIP), striatum (STR) and cortex (CTX) of wild-type or α-Syn A53T mice with or without renal failure (P = 0.0032 (spinal cord, WT Ctr vs. WT RF), P = 0.0025 (spinal cord, WT RF vs. A53T Ctr), P = 0.0002 (STR, WT Ctr vs. A53T RF), P = 0.0002 (STR, WT RF vs. A53T RF), P = 0.0001 (STR, A53T Ctr vs. A53T RF), P < 0.0001 (spinal cord: WT Ctr vs. A53T RF, WT RF vs. A53T RF, SNc, BLA, HIP, CTX)). c, Heatmap showing the extent of α-Syn pathology in the brains of α-Syn A53T mice with or without renal failure. d, HPLC analysis of DA, DOPAC and HVA in the striatum of wild-type or α-Syn A53T mice with or without renal failure (DA: P = 0.0485 (WT Ctr vs. A53T RF), P = 0.0264 (WT RF vs. A53T RF), P = 0.0309 (A53T Ctr vs. A53T RF), DOPAC: P = 0.0099 (WT Ctr vs. A53T RF), P = 0.0309 (WT RF vs. A53T RF), P = 0.0360 (A53T Ctr vs. A53T RF), HVA: P = 0.0176 (WT Ctr vs. A53T RF), P = 0.0149 (WT RF vs. A53T RF), P = 0.0416 (A53T Ctr vs. A53T RF)). Error bars indicate the mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001, n = 5 mice per group. For b, one-way ANOVA. For d, the Kruskal–Wallis test was used. AU, arbitrary units.
Extended Data Fig. 7 α-Syn spreads through kidney–brain neuronal pathways.
a, Representative images and schematic diagram of FG-labeled neural pathways innervating the kidney. b, Immunohistochemistry of pα-Syn in α-Syn A53T mice injected with α-Syn PFFs and PRV. DRG, dorsal root ganglia; IML, intermediolateral nucleus; NTS, solitary tract; RVL, rostroventrolateral reticular nucleus; LC, locus coeruleus; PCRt, parvicellular reticular nucleus; PVN, paraventricular nucleus. Scale bars: 100 μm (a) and 20 μm (b).
Extended Data Fig. 8 Intrarenal injection of α-Syn PFFs promotes α-Syn pathology in α-Syn A53T mice detected by pα-Syn antibody.
a, Timeline of the experiments. b, Quantification of immunohistochemistry in Fig. 5a showing the levels of pα-Syn in the kidney, spinal cord, locus coeruleus (LC), substantia nigra compacta (SNc), basolateral amygdala (BLA), hippocampus (HIP), striatum (STR), cortex (CTX) and olfactory bulb (OB) of α-Syn A53T mice that received intrarenal injection of PBS or α-Syn PFFs (P < 0.0001). RD, renal denervation; AU, arbitrary units. c, Heatmap showing the propagation of α-Syn inclusions in the brain of α-Syn A53T mice that received intrarenal injection of PBS or α-Syn PFFs. d, Double immunofluorescence of ubiquitin and pα-Syn in the striatum (P < 0.0001). Error bars indicate the mean ± s.e.m. ***P < 0.001. n = 5 mice per group, one-way ANOVA was used. AFU, arbitrary fluorescence units. Scale bars: 20 μm.
Extended Data Fig. 9 Intrarenal injection of α-Syn PFFs promotes α-Syn pathology in wild-type mice.
a,b, Immunohistochemistry of pα-Syn in the kidney, spinal cord, locus coeruleus (LC), substantia nigra compacta (SNc), basolateral amygdala (BLA), hippocampus (HIP), striatum (STR), cortex (CTX) and olfactory bulb (OB) of wild-type mice that received intrarenal injection of PBS or α-Syn PFFs (P = 0.0124 (kidney, PFFs 6m vs. RD + PFFs 6m), P = 0.0002 (STR), P < 0.0001 (kidney: PFFs 6m vs. PBS 6m, spinal cord, LC, SNc, BLA, HIP, CTX, OB)). Arrowheads: pα-Syn-positive signals. c, Western blot analysis of pα-Syn in the RIPA-soluble and RIPA-insoluble fractions of the spinal cord (left) and cortex (right) of wild-type mice injected with PBS or α- PFFs, respectively (P < 0.0001). Error bars indicate the mean ± s.e.m. *P < 0.05, ***P < 0.001. n = 5 mice per group, one-way ANOVA was used. AU, arbitrary units; RD, renal denervation. Scale bars: 20 μm.
Extended Data Fig. 10 Transplantation with Snca−/− bone marrow failed to reverse α-Syn pathology in mice that received intravenous injection of α-Syn PFFs.
a, Immunohistochemistry of pα-Syn in the glomeruli, spinal cord, basolateral amygdala (BLA), hippocampus (HIP), striatum (STR) and cortex (CTX) of control mice or mice with renal failure that were injected with α-Syn monomers or PFFs after being transplanted with bone marrow of Snca−/− mice. Arrowheads: pα-Syn-positive signals. b, Quantification of pα-Syn pathology in the mouse brain. The data without BMT are the same as those in Extended Data Fig. 4a (P = 0.0110 (spinal cord, without BMT, RF + monomers vs. RF + PFFs), P = 0.0078 (spinal cord, without BMT, PFFs vs. RF + PFFs), P < 0.0001 (spinal cord, without BMT, monomers vs. RF + PFFs), P = 0.0005 (STR, without BMT, PFFs vs. RF + PFFs), P < 0.0001 (STR, without BMT: monomers vs. RF + PFFs, RF + monomers vs. RF + PFFs), P = 0.0004 (CTX, without BMT, RF + monomers vs. RF + PFFs), P = 0.0014 (CTX, without BMT, PFFs vs. RF + PFFs), P < 0.0001 (CTX, without BMT: monomers vs. RF + PFFs), P < 0.0001 (glomeruli, renal medulla, SN, BLA, HIP)). Error bars indicate the mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001. n = 5 mice per group, two-way ANOVA was used. AU, arbitrary units; BMT, bone marrow transplantation. Scale bars: 20 μm.
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Source Data Figs. 1–6
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Source Data Extended Data Figs. 1–10
Statistical source data of Extended Data Figs. 1–10.
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Yuan, X., Nie, S., Yang, Y. et al. Propagation of pathologic α-synuclein from kidney to brain may contribute to Parkinson’s disease. Nat Neurosci 28, 577–588 (2025). https://doi.org/10.1038/s41593-024-01866-2
Received: 24 November 2022
Accepted: 05 December 2024
Published: 23 January 2025
Issue Date: March 2025
DOI: https://doi.org/10.1038/s41593-024-01866-2
