Can the Kidneys Kickstart Parkinson’s?

Could synucleinopathies start in the kidneys? In the January 23 Nature Neuroscience, scientists led by Zhentao Zhang at Wuhan University, China, report that, in people with Parkinson’s and Lewy body diseases, α-synuclein accumulates in these organs. What’s more, the same happens in people with chronic renal failure, even without any sign of PD or LBD. The authors also found that, in mice, α-synuclein pathology can pass from the kidney to the brain, triggering neuron loss and motor deficits. All told, these findings suggest a link between kidney dysfunction and LBDs.

  • Phosphorylated α-synuclein reported to accumulate in the kidneys of people with synucleinopathies.
  • Ditto for chronic kidney disease.
  • In mice, α-synuclein pathology spreads from the kidneys to the brain.

Some scientists were skeptical. For example, Thomas Beach, Banner Health, Phoenix, considers some of the data less than persuasive.

The hypothesis that PD originates in peripheral organs is not new. In 2003, Heiko Braak and Kelly Del Tredici, from the University of Ulm, Germany, identified α-synuclein inclusions in postmortem samples of the gastrointestinal tract from people who had had PD. They suggested that these aggregates might spread from the gut to the brain via neural pathways (Braak et al., 2003; Jul 2011 news series).

Building on this idea, Zhang and colleagues investigated the kidneys. First author Xin Yuan stained sections for antibodies to synuclein phosphorylated on serine 129, a post-translational modification associated with synuclein aggregation. Seven out of eight PD cases, as well as all three DLB cases, had phospho-synuclein deposits in their kidneys, while healthy controls did not (image below). Additionally, p-129 α-synuclein dotted the kidneys of 17 of 20 people with chronic kidney disease (CKD). Seven of them also had Lewy body- and Lewy neurite-like inclusions in the spinal cord, midbrain, and amygdala. A second antibody, Syn303, which binds oligomers and aggregates, also recognized deposits in the kidneys. These stained with thioflavin S, a ligand that binds to β-sheet structures found in amyloids, including α-synuclein fibrils. The authors propose that pathological α-synuclein may accumulate in the kidneys before the brain and before neurological symptoms appear.

Beach was unconvinced by the photomicrographs of phospho-synuclein in the brain and kidney. He wondered if the thioflavin S the authors used to detect fibrils might pick up other proteins with β-sheet structure, including collagens (comment below).

Kidney Trouble? Kidneys from a representative healthy control (top) are devoid of p-129 synuclein deposits (green). A kidney from a PD case is speckled with them (green, bottom right). Unphosphorylated synuclein shows as purple. [Courtesy of Yuan et al., Nature Neuroscience.]

To investigate further, the scientists turned to animal models. Yuan injected 3-month-old wild-type mice once with doxorubicin, a chemotherapy agent commonly used in experimental models to induce kidney failure, then injected α-synuclein preformed fibrils (PFFs) intravenously every two weeks over the course of three months. At 6 months old, treated mice had abundant α-synuclein deposits in the kidneys and in the central nervous system, including the spinal cord, hippocampus, striatum, and cortex. The treated mice also had fewer neurons in the midbrain than did untreated controls, and they crawled unsteadily along a narrow balance beam. By contrast, mice injected with fibrils, but not doxorubicin, had modest synuclein pathology in kidneys and brain and no loss of motor control.

Both the human and mouse data hint that poorly functioning kidneys enable local buildup of α-synuclein. Does it stay put or spread to the brain? To find out, Yuan injected PFFs directly into kidneys of 3-month-old A53T mice, which overexpress a form of human α-synuclein that is prone to aggregate. Within three months, phosphorylated α-synuclein had spread throughout the brain. These mice lost dopaminergic neurons in the substantia nigra and striatum, areas most ravaged by Parkinson’s (image below). “With more than 10 years of PFF research, this is one of the first reports I have seen showing human PFFs might kill dopaminergic neurons in wild-type mice, albeit this appears to be restricted to renal failure mice,” noted Andrew West, Duke university, Durham, North Carolina. If this result can be replicated, it could be a useful model, he added, though he thinks some of the experiments are difficult to interpret.

How did the synuclein get to the brain? Thinking it might have travelled through nerves that innervate the kidney, the scientists ablated those nerves in mice, then injected synuclein fibrils directly into their kidneys. (Renal sympathetic denervation has been reported to protect kidneys from cellular senescence and fibrosis; Li et al., 2021.) This confined α-synuclein pathology to the peripheral organs. No deposits or neurodegeneration appeared in the CNS. Renal-denervated mice also stayed atop a narrow beam and climbed a pole more proficiently than did mice with intact kidney-brain neuronal connections.

Stop the Spread. Injecting saline into mouse kidneys did not affect the left or right substantia nigra (top). Injecting fibrils of α-synuclein ablated about half of the dopaminergic neurons (middle panels); severing kidney-brain neuronal connections prevented this (lower panels). [Courtesy of Yuan et al., Nature Neuroscience.]

Synuclein injections had the same effect in wild-type mice, albeit over a longer incubation period. Six months after injecting the fibrils, the animals had developed CNS pathology and lost dopaminergic neurons in the midbrain. Here too, renal denervation prevented PD-like pathology. Zhang’s findings echo those of previous work by Ted Dawson and Han Seok Ko, Johns Hopkins University, Baltimore, who found that injecting α-synuclein fibrils into the gut induced brain pathology, but not if they cut the vagus nerve (Kim et al., 2019).

Zhang’s data might help explain reports that people with end-stage renal disease or CKD are more likely to develop PD, while those who receive kidney transplants have a reduced risk (Baek et al., 2021; Wang et al., 2014; Nam et al., 2019). 

To Beach’s mind this connection may be weak. He oversees the Arizona Study of Aging and Neurodegenerative Disorders, which includes a large brain and body donation program. “A search of our database … indicates that renal failure is actually more common amongst control subjects than in those with clinicopathologically diagnosed PD or DLB,” he wrote (Beach et al., 2015).—George Heaton

George Heaton is a freelance writer in Durham, North Carolina.

Comments

    • User Profile Image Thomas Beach
      Banner Sun Health Research Institute
    • Posted:

    The authors claim to have found p-synuclein IHC-positive nerve fibers in 10 of 11 patients with PD or DLB, and also in 17 patients who had chronic kidney disease, seven of whom also had CNS p-synuclein “pathology.” The photomicrographs are not morphologically convincing, especially those that purport to show positive pSyn staining in the spinal cord, amygdala, and midbrain of CKD patients, while some of the positive pSyn staining in the kidneys seems to be within kidney tubule epithelial cells (Fig 1f). In the RF mice, Fig 4a, much of the staining in brain cells appears to be within nuclei.

    The thioflavin S findings are difficult to interpret as many structures can be thioflavin-S-positive in peripheral structures, including collagen fibers. Similarly, the seeding assay findings are difficult to interpret as they could have been affected by β-pleated sheet sequences in peripheral proteins, again including collagens.   

    The authors claim that the kidney mediates the clearance of circulating α-synuclein, yet the 24-hour amounts found in the urine do not differ between control and renal failure mice. On the other hand, the blood half-life of α-synuclein is longer in the renal failure mice. This suggests that the α-synuclein, if metabolized by the kidney, is metabolized enzymatically in the cortical kidney tubules, or perhaps in another organ such as the liver. The authors do not mention whether the liver also has reduced function in the renal failure mice. For these reasons, it seems an overstatement to say that “The kidney mediates the clearance of circulating α-syn."

    The transmission of injected PFFs from kidney to brain is not surprising given that many groups have shown that peripherally injected PFFs can spread to brain. It is still controversial whether this actually occurs in human Lewy body diseases, or whether in fact the spread is from brain to periphery. Autopsies of humans with or without Lewy body disease indicate that α-synuclein pathology is rarely, if ever, found in extra-CNS regions in persons who do not have such pathology in the brain, indicating that the original site of α-synuclein pathology is most likely in the brain and not in the body (Beach et al., 2021). Such studies also have indicated that the kidney is less likely than other peripheral organs to have pSyn pathology in subjects with demonstrated CNS Lewy body disease (Beach et al., 2010).

    A search of our database (Arizona Study of Aging and Neurodegenerative Disorders (Beach et al., 2015) indicates that renal failure is actually more common amongst control subjects than in those with clinicopathologically diagnosed PD or DLB. Chronic renal failure was a medical history condition in 267 of 540 (49.4 percent) control subjects versus 84/305 (27.5 control) PD subjects and 66/203(32.5 percent) DLB subjects. Comparing these rates, control subjects are significantly more likely to have renal failure than are either PD or DLB subjects (chi-square p > 0.0001 for both comparisons).

    References:

    Beach TG, Adler CH, Sue LI, Shill HA, Driver-Dunckley E, Mehta SH, Intorcia AJ, Glass MJ, Walker JE, Arce R, Nelson CM, Serrano GE. Vagus Nerve and Stomach Synucleinopathy in Parkinson's Disease, Incidental Lewy Body Disease, and Normal Elderly Subjects: Evidence Against the "Body-First" Hypothesis. J Parkinsons Dis. 2021;11(4):1833-1843. PubMed.

    Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, Akiyama H, Caviness JN, Shill HA, Sabbagh MN, Walker DG, . Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol. 2010 Jun;119(6):689-702. PubMed.

    Beach TG, Adler CH, Sue LI, Serrano G, Shill HA, Walker DG, Lue L, Roher AE, Dugger BN, Maarouf C, Birdsill AC, Intorcia A, Saxon-Labelle M, Pullen J, Scroggins A, Filon J, Scott S, Hoffman B, Garcia A, Caviness JN, Hentz JG, Driver-Dunckley E, Jacobson SA, Davis KJ, Belden CM, Long KE, Malek-Ahmadi M, Powell JJ, Gale LD, Nicholson LR, Caselli RJ, Woodruff BK, Rapscak SZ, Ahern GL, Shi J, Burke AD, Reiman EM, Sabbagh MN. Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program. Neuropathology. 2015 Aug;35(4):354-89. Epub 2015 Jan 26 PubMed.

    View all comments by Thomas Beach

  2. Yuan et al. found that intravenous injection of α-syn preformed fibrils induced α-syn pathology, which was exacerbated by renal failure. Intrarenal injection of α-syn PFFs induced α-syn deposition in both the kidney and brain. The authors found that both α-syn monomers and fibrils in the plasma are quickly degraded in normal kidneys. In cases of renal failure, pathological α-syn may not be eliminated efficiently and may deposit in the kidney and then spread to the brain. Indeed, extensive α-syn pathology was observed in the kidney, spinal cord, and brain of patients with chronic kidney diseases (CKD) without parkinsonism, indicating that these patients may represent the presymptomatic stage of PD, although more likely they represent people at risk. The authors acknowledge they were inspired by our previous work, showing that intrastriatal or enteric nervous system injection of patient-derived α-syn did not induce pathology in the vagus nerve (Arotcarena et al., 2020).

    The study is tantalizing and brings new evidence for the non-neuronal pathway of α-syn pathology spread in the body, pointing toward the body-first hypothesis; there are clear cases of brain-first Parkinson’s disease as well (see Horsager and Borghammer, 2024). A more balanced view, integrating contradictory results and demonstrating no blood contamination using patient-derived α-Syn aggregates in parabiosis experiments (Yu et al., 2021) would be needed.

    It remains that the study brings novel evidence supporting that multiple pathways, both neuronal and nonneuronal, may exist for transmitting pathological aggregated α-Syn from the periphery to the brain in individuals with PD.

    References:

    Arotcarena ML, Dovero S, Prigent A, Bourdenx M, Camus S, Porras G, Thiolat ML, Tasselli M, Aubert P, Kruse N, Mollenhauer B, Trigo Damas I, Estrada C, Garcia-Carrillo N, Vaikath NN, El-Agnaf OM, Herrero MT, Vila M, Obeso JA, Derkinderen P, Dehay B, Bezard E. Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates. Brain. 2020 May 1;143(5):1462-1475. PubMed.

    Horsager J, Borghammer P. Brain-first vs. body-first Parkinson's disease: An update on recent evidence. Parkinsonism Relat Disord. 2024 May;122:106101. Epub 2024 Mar 15 PubMed.

    Yu X, Persillet M, Zhang L, Zhang Y, Xiuping S, Li X, Ran G, Breger LS, Dovero S, Porras G, Dehay B, Bezard E, Qin C. Evaluation of blood flow as a route for propagation in experimental synucleinopathy. Neurobiol Dis. 2021 Mar;150:105255. Epub 2021 Jan 7 PubMed.

    View all comments by Erwan Bezard
    • User Profile Image Valina Dawson
      Johns Hopkins University School of Medicine Institute for Cell Engineering
    • Posted:

    This is an interesting story. There are undoubtedly many ‘body first’ opportunities for synuclein to misfold and reach a threshold where pathologic synuclein can move to the brain and initiate disease. We are in the early stages of understanding this process. Increasing our depth and breadth of knowledge will ultimately improve the diagnosis and management of PD patients.

    View all comments by Valina Dawson

  4. I'd like to offer a clarification relevant to my quote in this great article. I have subsequently been informed that the α-syn PFFs used may have been mixed through the study—possibly human sequence, mouse, or some combination.

    As I can understand the bulk of the observations in this paper, which is of high interest, the main in vivo model appears to include endpoints resultant from interactions between endogenous mouse α-syn, mutated (overexpressed, mislocalized) human A53T α-syn, and injected exogenous human PFFs (unknown polymorphic structure), all interacting together to combine into a presumptive generalized α-syn mechanism, something presumed relevant not only to native function, but to CNS pathobiology.

    One issue to contribute to the discussion here relates to what I consider an endemic problem the field faces in interpreting biological outcomes, like the role of kidneys in α-synucleinopathy, in the α-synuclein modeling space. Findings from our own group (Sokratian et al., 2024), and many others (Peng et al., 2018; Long et al., 2021; Uemura et al., 2023; Van der Perren et al., 2020), demonstrate vastly different pathological properties associated with even slight polymorphic structural variances in α-syn, even when the α-syn sequence is the same between conformers. Assuming structural features are important, then without knowledge of what was used in any particular study replication becomes all the more unlikely, perhaps even futile. That a study can be published where even the sequence of the α-syn proteins used is in question, much less the structural conformers known to drive pathobiology, speaks to a field wide deficit, all the way from experimental design to our review and editorial process.

    Hopefully, with time, our models can get closer and closer to what is happening in the human brain, but without basic reporting standards, it is hard to know the direction the field might be moving in this regard.   

    References:

    Sokratian A, Zhou Y, Tatli M, Burbidge KJ, Xu E, Viverette E, Donzelli S, Duda AM, Yuan Y, Li H, Strader S, Patel N, Shiell L, Malankhanova T, Chen O, Mazzulli JR, Perera L, Stahlberg H, Borgnia M, Bartesaghi A, Lashuel HA, West AB. Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases. Sci Adv. 2024 Nov;10(44):eadq3539. Epub 2024 Nov 1 PubMed.

    Peng C, Gathagan RJ, Lee VM. Distinct α-Synuclein strains and implications for heterogeneity among α-Synucleinopathies. Neurobiol Dis. 2018 Jan;109(Pt B):209-218. Epub 2017 Jul 24 PubMed.

    Long H, Zheng W, Liu Y, Sun Y, Zhao K, Liu Z, Xia W, Lv S, Liu Z, Li D, He KW, Liu C. Wild-type α-synuclein inherits the structure and exacerbated neuropathology of E46K mutant fibril strain by cross-seeding. Proc Natl Acad Sci U S A. 2021 May 18;118(20) PubMed.

    Uemura N, Marotta NP, Ara J, Meymand ES, Zhang B, Kameda H, Koike M, Luk KC, Trojanowski JQ, Lee VM. α-Synuclein aggregates amplified from patient-derived Lewy bodies recapitulate Lewy body diseases in mice. Nat Commun. 2023 Oct 28;14(1):6892. PubMed.

    Van der Perren A, Gelders G, Fenyi A, Bousset L, Brito F, Peelaerts W, Van den Haute C, Gentleman S, Melki R, Baekelandt V. The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson's disease, multiple system atrophy and dementia with Lewy bodies. Acta Neuropathol. 2020 Jun;139(6):977-1000. Epub 2020 Apr 30 PubMed.

    View all comments by Andrew West

  5. This fascinating study builds on recent research that highlights the underappreciated role of ⍺-synuclein in the periphery and its involvement in PD pathogenesis. While ⍺-synuclein is often considered a brain protein, it is more abundant in the periphery, particularly in blood.

    Systemic levels of synuclein are prone to change as the protein increases in response to inflammatory insults. This can happen during infections, either through immune activity or hemolysis (Mercado et al., 2024). Experimental models have shown that these changes can be transient and short-lived. However, we still do not fully understand how ⍺-synuclein levels in the blood are regulated, how they increase and, importantly, how they return to normal. Although its diagnostic value might be limited (Zubelzu et al., 2022), understanding this regulation is crucial, because an abundance of peripheral ⍺-synuclein could potentially influence protein levels in the CNS.

    This study demonstrates that the kidneys, unlike other peripheral organs, play an important role in this process. This occurs through the action of various cathepsins expressed in the kidneys, which efficiently degrade both soluble and insoluble recombinant ⍺-synuclein.

    The authors went to great lengths, using wild-type, transgenic, and bone marrow transplantation models, to show that pathology can originate in the kidneys and subsequently spread to the CNS, where it may contribute to disease progression in these experimental models. This transmission could occur through parasympathetic or sympathetic connections, or via systemic pathways.

    But what does this all mean in the context of idiopathic PD? There is still much more to find out, but this study suggests that (chronic) kidney pathology could be a potential risk factor for PD. This comes after other recent evidence that urinary tract infections can be a risk factor of PD (Cocoros et al., 2021) and MSA (Peelaerts et al., 2023). These links, and how pathology might propagate in a cell-autonomous or -non-autonomous manner, need to be understood. Genetic and environmental risk factors likely play a role in facilitating the initial steps of protein aggregation, or the spread of ⍺-synuclein from the periphery to the brain, and now this study provides clues into how this process might occur.

    References:

    Mercado G, Kaeufer C, Richter F, Peelaerts W. Infections in the Etiology of Parkinson's Disease and Synucleinopathies: A Renewed Perspective, Mechanistic Insights, and Therapeutic Implications. J Parkinsons Dis. 2024;14(7):1301-1329. PubMed.

    Zubelzu M, Morera-Herreras T, Irastorza G, Gómez-Esteban JC, Murueta-Goyena A. Plasma and serum alpha-synuclein as a biomarker in Parkinson's disease: A meta-analysis. Parkinsonism Relat Disord. 2022 Jun;99:107-115. Epub 2022 Jun 8 PubMed.

    Cocoros NM, Svensson E, Szépligeti SK, Vestergaard SV, Szentkúti P, Thomsen RW, Borghammer P, Sørensen HT, Henderson VW. Long-term Risk of Parkinson Disease Following Influenza and Other Infections. JAMA Neurol. 2021 Dec 1;78(12):1461-1470. PubMed.

    Peelaerts W, Mercado G, George S, Villumsen M, Kasen A, Aguileta M, Linstow C, Sutter AB, Kuhn E, Stetzik L, Sheridan R, Bergkvist L, Meyerdirk L, Lindqvist A, Gavis ML, Van den Haute C, Hultgren SJ, Baekelandt V, Pospisilik JA, Brudek T, Aznar S, Steiner JA, Henderson MX, Brundin L, Ivanova MI, Hannan TJ, Brundin P. Urinary tract infections trigger synucleinopathy via the innate immune response. Acta Neuropathol. 2023 May;145(5):541-559. Epub 2023 Mar 30 PubMed.

    View all comments by Wouter Peelaerts

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References

Series Citations

  1. A Contentious Hypothesis About Where and How PD Starts

Antibody Citations

  1. α-Synuclein

Research Models Citations

  1. α-synuclein A53T Mouse (Tg)

Paper Citations

  1. Braak H, Del Tredici K, Rüb U, De Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211. PubMed.
  2. Li Q, Deng Y, Liu L, Zhang C, Cai Y, Zhang T, Han M, Xu G. Sympathetic Denervation Ameliorates Renal Fibrosis via Inhibition of Cellular Senescence. Front Immunol. 2021;12:823935. Epub 2022 Jan 24 PubMed.
  3. Kim S, Kwon SH, Kam TI, Panicker N, Karuppagounder SS, Lee S, Lee JH, Kim WR, Kook M, Foss CA, Shen C, Lee H, Kulkarni S, Pasricha PJ, Lee G, Pomper MG, Dawson VL, Dawson TM, Ko HS. Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease. Neuron. 2019 Aug 21;103(4):627-641.e7. Epub 2019 Jun 26 PubMed.
  4. Baek SH, Park S, Yu MY, Kim JE, Park SH, Han K, Kim YC, Kim DK, Joo KW, Kim YS, Lee H. Incident Parkinson's disease in kidney transplantation recipients: a nationwide population-based cohort study in Korea. Sci Rep. 2021 May 18;11(1):10541. PubMed.
  5. Wang IK, Lin CL, Wu YY, Chou CY, Lin SY, Liu JH, Yen TH, Huang CC, Sung FC. Increased risk of Parkinson's disease in patients with end-stage renal disease: a retrospective cohort study. Neuroepidemiology. 2014;42(4):204-10. Epub 2014 Apr 15 PubMed.
  6. Nam GE, Kim NH, Han K, Choi KM, Chung HS, Kim JW, Han B, Cho SJ, Jung SJ, Yu JH, Park YG, Kim SM. Chronic renal dysfunction, proteinuria, and risk of Parkinson's disease in the elderly. Mov Disord. 2019 Aug;34(8):1184-1191. Epub 2019 Apr 25 PubMed.
  7. Beach TG, Adler CH, Sue LI, Serrano G, Shill HA, Walker DG, Lue L, Roher AE, Dugger BN, Maarouf C, Birdsill AC, Intorcia A, Saxon-Labelle M, Pullen J, Scroggins A, Filon J, Scott S, Hoffman B, Garcia A, Caviness JN, Hentz JG, Driver-Dunckley E, Jacobson SA, Davis KJ, Belden CM, Long KE, Malek-Ahmadi M, Powell JJ, Gale LD, Nicholson LR, Caselli RJ, Woodruff BK, Rapscak SZ, Ahern GL, Shi J, Burke AD, Reiman EM, Sabbagh MN. Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program. Neuropathology. 2015 Aug;35(4):354-89. Epub 2015 Jan 26 PubMed.

Further Reading

Papers

  1. Braak H, Del Tredici K, Rüb U, De Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211. PubMed.
  2. Baek SH, Park S, Yu MY, Kim JE, Park SH, Han K, Kim YC, Kim DK, Joo KW, Kim YS, Lee H. Incident Parkinson's disease in kidney transplantation recipients: a nationwide population-based cohort study in Korea. Sci Rep. 2021 May 18;11(1):10541. PubMed.
  3. Wang IK, Lin CL, Wu YY, Chou CY, Lin SY, Liu JH, Yen TH, Huang CC, Sung FC. Increased risk of Parkinson's disease in patients with end-stage renal disease: a retrospective cohort study. Neuroepidemiology. 2014;42(4):204-10. Epub 2014 Apr 15 PubMed.
  4. Nam GE, Kim NH, Han K, Choi KM, Chung HS, Kim JW, Han B, Cho SJ, Jung SJ, Yu JH, Park YG, Kim SM. Chronic renal dysfunction, proteinuria, and risk of Parkinson's disease in the elderly. Mov Disord. 2019 Aug;34(8):1184-1191. Epub 2019 Apr 25 PubMed.
  5. Kim S, Kwon SH, Kam TI, Panicker N, Karuppagounder SS, Lee S, Lee JH, Kim WR, Kook M, Foss CA, Shen C, Lee H, Kulkarni S, Pasricha PJ, Lee G, Pomper MG, Dawson VL, Dawson TM, Ko HS. Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease. Neuron. 2019 Aug 21;103(4):627-641.e7. Epub 2019 Jun 26 PubMed.

Primary Papers

  1. Yuan X, Nie S, Yang Y, Liu C, Xia D, Meng L, Xia Y, Su H, Zhang C, Bu L, Deng M, Ye K, Xiong J, Chen L, Zhang Z. Propagation of pathologic α-synuclein from kidney to brain may contribute to Parkinson's disease. Nat Neurosci. 2025 Jan 23; Epub 2025 Jan 23 PubMed.

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