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Propagation of pathologic α-synuclein from kidney to brain may contribute to Parkinson’s disease

Nature Neuroscience volume 28, pages 577–588 (2025) Cite this article

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Abstract

The pathogenesis of Lewy body diseases (LBDs), including Parkinson’s disease (PD), involves α-synuclein (α-Syn) aggregation that originates in peripheral organs and spreads to the brain. PD incidence is increased in individuals with chronic renal failure, but the underlying mechanisms remain unknown. Here we observed α-Syn deposits in the kidneys of patients with LBDs and in the kidney and central nervous system of individuals with end-stage renal disease without documented LBDs. In male mice, we found that the kidney removes α-Syn from the blood, which is reduced in renal failure, causing α-Syn deposition in the kidney and subsequent spread into the brain. Intrarenal injection of α-Syn fibrils induces the propagation of α-Syn pathology from the kidney to the brain, which is blocked by renal denervation. Deletion of α-Syn in blood cells alleviates pathology in α-Syn A53T transgenic mice. Thus, the kidney may act as an initiation site for pathogenic α-Syn spread, and compromised renal function may contribute to the onset of LBDs.

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Fig. 1: α-Syn pathology in the kidneys and CNS of patients with PD and CKD.
The alternative text for this image may have been generated using AI.
Fig. 2: Physiological clearance of α-Syn by the kidney.
The alternative text for this image may have been generated using AI.
Fig. 3: RF exacerbates α-Syn pathology induced by intravenous injection of α-Syn PFFs.
The alternative text for this image may have been generated using AI.
Fig. 4: RF promotes α-Syn pathology in α-Syn A53T mice.
The alternative text for this image may have been generated using AI.
Fig. 5: Intrarenal injection of α-Syn PFFs promotes α-Syn pathology in α-Syn A53T mice.
The alternative text for this image may have been generated using AI.
Fig. 6: Transplantation of Snca−/− bone marrow ameliorates PD-like pathology in α-Syn A53T mice.
The alternative text for this image may have been generated using AI.

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Data availability

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.

Code availability

No unique code was generated in 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.).

Author information

Author notes

  1. These authors contributed equally: Xin Yuan, Shuke Nie, Yingxu Yang.

Authors and Affiliations

  1. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China

    Xin Yuan, Shuke Nie, Yingxu Yang, Congcong Liu, Danhao Xia, Lanxia Meng, Min Deng, Jing Xiong & Zhentao Zhang

  2. Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China

    Yue Xia

  3. Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Hua Su & Chun Zhang

  4. PET–CT/MRI Center, Faculty of Radiology and Nuclear Medicine, Renmin Hospital of Wuhan University, Wuhan, China

    Lihong Bu

  5. Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Shenzhen, China

    Keqiang Ye

  6. Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA

    Liam Chen

  7. TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China

    Zhentao Zhang

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Contributions

Z.Z. conceived and supervised the project. X.Y. performed most of the experiments. S.N., Y.X. and L.C. performed the immunostaining of human sections. Y.Y., C.L., D.X., L.M., J.X., L.B. and M.D. helped with the cell culture and animal experiments. H.S. and C.Z. collected serum and urine samples. K.Y. helped in the data interpretation.

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Correspondence to Zhentao Zhang.

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Nature Neuroscience thanks Veerle Baekelandt, Han Seok Ko and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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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).

Source data

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).

Source data

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).

Source data

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.

Source data

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.

Source data

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.

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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).

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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.

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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.

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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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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

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