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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Banner Sun Health Research Institute
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 BeachUniversity of Bordeaux
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 BezardJohns Hopkins University School of Medicine Institute for Cell Engineering
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 DawsonDuke University
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 WestKU Leuven
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.
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