As Parkinson’s Progresses, Do Synuclein Fibrils Shape-Shift?
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Fibrils of α-synuclein may be the common denominator among the synucleinopathies, but they do not all map to the same blueprint. Fibrils from people who have multiple system atrophy fold differently from those found in Parkinson’s, Parkinson’s disease dementia, and dementia with Lewy bodies. If unique fibrils can form in different diseases, might specific conformations also emerge at different stages of a single disease? Yes, say scientists led by Dan Li at Shanghai Jiao Tong University and Jian Wang at Fudan University, also in Shanghai.
- Synuclein fibrils amplified from cerebrospinal fluid.
- One conformation abounds at all stages of Parkinson’s.
- A minor conformer from only late-stage CSF potently seeds new fibrils.
In the December 12 Structure, they report a conformer from a person with late-stage Parkinson’s that was not detected in others in mid- or preclinical disease stage. The findings hint that α-synuclein fibrils undergo a conformational transition as the disease progresses. Scientists have wondered if other amyloids, including Aβ and tau fibrils, might also shape-shift over time.
Shifting Synucleins. In Parkinson’s, the most abundant α-synuclein polymorphs are the same throughout disease progression. Minor polymorphs, however, are different. The variant most toxic to neurons emerges in late-stage PD. [Courtesy of Fan et al., Structure, 2022.]
To be clear, joint first authors Yun Fan at Fudan University and Yunpeng Sun at Shanghai Institute of Organic Chemistry did not isolate fibrils from brain tissue, as recent cryo-EM studies were able to do. They used a technique developed by Claudio Soto’s group at the University of Texas to spur the growth of protofibrils using cerebrospinal fluid as a seed (Shahnawaz et al., 2020).
They tested CSF from four healthy controls, from one person with preclinical PD, four with mid-stage PD, and one person with late-stage disease. The protein misfolding cyclic amplification (PMCA) method yielded no fibrils from control CSF, but all six PD samples seeded synuclein aggregates. When the scientists examined these fibrils by cryo-EM they found one major polymorph at all stages of disease (see image below). It folds similarly to synuclein fibrils made in vitro (Guerrero-Ferreira et al., 2019).
Morphing Polymorphs. Major synuclein polymorphs from all disease stages were identical (left), comprising two left-handed helices (purple and gold) that wrap around each other. The minor polymorph from mid-stage PD (center) had almost identical protofibrils (brown and blue) to that of the major forms, but they wrapped around each other in a different conformation. The minor polymorph from late-stage PD (right), had a unique fold; two identical protofibrils (cyan) embraced each other to form fibrils. [Courtesy of Fan et al., Structure, 2022]
The minor polymorphs were more interesting. In mid-stage PD, these were very similar to the major polymorphs, adopting the same folds but wrapping around each other differently to form fibrils (see image above).
The minor form from late PD was completely different. Doublets of a single protofibril embraced to form fibrils, forming a structure that has not been reported before. Still, these protofibrils adopted folds substantially similar to those seen in fibrils Li previously made in vitro, and with folds found in synuclein isolated from the brains of people with multiple system atrophy (Li et al., 2018; Mar 2020 news). Differences include a more elongated C-terminal in the late-stage amplified variant versus the MSA structure and a β-hairpin at residues 59-72 in the PMCA protofibril with side chains flipped 180 degrees (see image below). The authors note that the MSA fibrils incorporate post-translational modifications and mysterious co-factors that might not be fully captured by the PMCA amplification, hence it may not fully represent the parent conformer that lurks in the brain.
PD á la MSA? The minor polymorph amplified from late-stage PD CSF (cyan) folds similarly (top left) to synuclein protofibrils isolated from MSA brain tissue (gray) or amplified from MSA fibrils (purple). Enlarged views i, ii, and iii show the major differences. [Courtesy of Fan et al., Structure, 2022.]
Does the late-stage PD polymorph reveal anything about disease progression? Curiously, the late-stage PMCA sample was the most toxic to neurons in culture, robustly inducing phosphorylation of endogenous α-synuclein and seeding new fibrils. Since this sample contained 27 percent minor polymorph, versus 8 percent to 17 percent for the pre- and mid-stage samples, the authors attributed this toxicity to the late-stage minor polymorph.—Tom Fagan
References
News Citations
Paper Citations
- Shahnawaz M, Mukherjee A, Pritzkow S, Mendez N, Rabadia P, Liu X, Hu B, Schmeichel A, Singer W, Wu G, Tsai AL, Shirani H, Nilsson KP, Low PA, Soto C. Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy. Nature. 2020 Feb;578(7794):273-277. Epub 2020 Feb 5 PubMed.
- Guerrero-Ferreira R, Taylor NM, Arteni AA, Kumari P, Mona D, Ringler P, Britschgi M, Lauer ME, Makky A, Verasdonck J, Riek R, Melki R, Meier BH, Böckmann A, Bousset L, Stahlberg H. Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy. Elife. 2019 Dec 9;8 PubMed.
- Li Y, Zhao C, Luo F, Liu Z, Gui X, Luo Z, Zhang X, Li D, Liu C, Li X. Amyloid fibril structure of α-synuclein determined by cryo-electron microscopy. Cell Res. 2018 Sep;28(9):897-903. Epub 2018 Jul 31 PubMed.
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MRC Laboratory of Molecular Biology
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MRC Laboratory of Molecular Biology
Fan et al. use PMCA to amplify α-synuclein seeds from cerebrospinal fluid of individuals from different clinical stages of Parkinson’s disease. They conclude that α-synuclein fibrils change conformation during different stages of Parkinson's disease. We consider that this conclusion is not supported by the data presented.
In vitro amplification experiments like PMCA, where aggregation of recombinant or synthetic protein is seeded with small amounts of aggregates, are often used to increase the amounts of detectable aggregates for subsequent analyses. However, until recently, no one had checked whether the structures of amyloid filaments formed during in vitro amplification experiments indeed replicate the structures of the initial seeds. When we used similar amplification procedures to the ones used by Fan et al., but with structurally characterized α-synuclein seeds from three brains with end-stage Multiple System Atrophy (MSA), we found that the structures formed during amplification were different from the structures of the initial seeds (Lövestam et al., 2021; Schweighauser et al., 2020). We concluded that amplification of α-synuclein seeds by PMCA does not necessarily replicate the structures of the seeds.
Recently, we also determined the structure of α-synuclein filaments from brains with end-stage Parkinson's disease and dementia with Lewy bodies, which we termed the Lewy fold (Yang et al., 2022). If these extraction methods are biased, they are all biased in the same way. The Lewy fold is different from the α-synuclein folds observed in MSA. We postulate that these folds are different conformers that characterise different diseases, much like we observed previously for tauopathies (Shi et al., 2021). Both the Lewy fold and the MSA folds are different from the PMCA products described by Lövestam et al. and by Fan et al.
Fan et al. argue that, like in vitro amplification, brain extraction of fibrils may be biased toward specific polymorphs. We cannot exclude the possibility that extraction of fibrils from brains may be biased. Not much work has been done for α-synuclein yet, but for tau filaments from brains with end-stage Alzheimer’s disease, three different extraction methods have so far yielded identical structures: sarkosyl solubilization of homogenized tissue (Fitzpatrick et al., 2017); of homogenized tissue without sarkosyl (Falcon et al., 2018); and soaking of sliced tissue in water (Stern et al., 2022). The latter method also yielded Aβ42 filaments with the same structures as those obtained using sarkosyl solubilization (Yang et al., 2022). If these extraction methods are biased, they are all biased in the same way.
However, all seven cryo-EM structures described by Fan et al, including the minor polymorphs they claim distinguish between mid and late stages of Parkinson’s disease, are similar to structures that we obtained using PMCA with end-stage MSA seeds. Therefore, we conclude that these structures are probably an artefact. Rather than representing differences in structures among the initial seeds, the amplified structures are likely the result of the specific in vitro assembly conditions used. Like we did, Fan et al. also based their PMCA experiments on conditions described by the Soto group.
Our observations do not mean that PMCA experiments should always be avoided. They might still be useful to distinguish between diseases, as proposed for example by the Soto group (Shahnawaz et al., 2020). However, when interpreting the actual structures formed during amplification, the possibility that these structures are different from the structures of the initial seeds should be considered. Possibly, the molecular mechanisms of templated seeding are not yet well understood. Therefore, in order to confirm whether α-synuclein fibrils indeed change conformation during different stages of Parkinson's disease, it will be necessary to perform experiments that do not involve amplification.
References:
Lövestam S, Schweighauser M, Matsubara T, Murayama S, Tomita T, Ando T, Hasegawa K, Yoshida M, Tarutani A, Hasegawa M, Goedert M, Scheres SH. Seeded assembly in vitro does not replicate the structures of α-synuclein filaments from multiple system atrophy. FEBS Open Bio. 2021 Apr;11(4):999-1013. Epub 2021 Feb 24 PubMed.
Schweighauser M, Shi Y, Tarutani A, Kametani F, Murzin AG, Ghetti B, Matsubara T, Tomita T, Ando T, Hasegawa K, Murayama S, Yoshida M, Hasegawa M, Scheres SH, Goedert M. Structures of α-synuclein filaments from multiple system atrophy. Nature. 2020 Sep;585(7825):464-469. Epub 2020 May 27 PubMed.
Yang Y, Shi Y, Schweighauser M, Zhang X, Kotecha A, Murzin AG, Garringer HJ, Cullinane PW, Saito Y, Foroud T, Warner TT, Hasegawa K, Vidal R, Murayama S, Revesz T, Ghetti B, Hasegawa M, Lashley T, Scheres SH, Goedert M. Structures of α-synuclein filaments from human brains with Lewy pathology. Nature. 2022 Oct;610(7933):791-795. Epub 2022 Sep 15 PubMed. bioRxiv. PubMed
Shi Y, Zhang W, Yang Y, Murzin AG, Falcon B, Kotecha A, van Beers M, Tarutani A, Kametani F, Garringer HJ, Vidal R, Hallinan GI, Lashley T, Saito Y, Murayama S, Yoshida M, Tanaka H, Kakita A, Ikeuchi T, Robinson AC, Mann DM, Kovacs GG, Revesz T, Ghetti B, Hasegawa M, Goedert M, Scheres SH. Structure-based classification of tauopathies. Nature. 2021 Oct;598(7880):359-363. Epub 2021 Sep 29 PubMed.
Fitzpatrick AW, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SH. Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. 2017 Jul 13;547(7662):185-190. Epub 2017 Jul 5 PubMed.
Falcon B, Zhang W, Schweighauser M, Murzin AG, Vidal R, Garringer HJ, Ghetti B, Scheres SH, Goedert M. Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold. Acta Neuropathol. 2018 Nov;136(5):699-708. Epub 2018 Oct 1 PubMed.
Stern AM, Yang Y, Meunier AL, Liu W, Cai Y, Ericsson M, Lei L, Goedert M, Scheres SH, Selkoe DJ. Abundant Aβ fibrils in ultracentrifugal supernatants of 2 aqueous extracts from Alzheimer’s disease brains. bioRxiv, October 18, 2022 bioRxiv
Yang Y, Arseni D, Zhang W, Huang M, Lövestam S, Schweighauser M, Kotecha A, Murzin AG, Peak-Chew SY, Macdonald J, Lavenir I, Garringer HJ, Gelpi E, Newell KL, Kovacs GG, Vidal R, Ghetti B, Ryskeldi-Falcon B, Scheres SH, Goedert M. Cryo-EM structures of amyloid-β 42 filaments from human brains. Science. 2022 Jan 14;375(6577):167-172. Epub 2022 Jan 13 PubMed.
Shahnawaz M, Mukherjee A, Pritzkow S, Mendez N, Rabadia P, Liu X, Hu B, Schmeichel A, Singer W, Wu G, Tsai AL, Shirani H, Nilsson KP, Low PA, Soto C. Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy. Nature. 2020 Feb;578(7794):273-277. Epub 2020 Feb 5 PubMed.
Emory University
The ability of aggregation-prone proteins to adopt different structural and functional conformations (referred to as proteopathic strains) could help to explain the stage-like progression of several neurodegenerative diseases. There is circumstantial evidence, for instance, that the proteins that incite prion disease (Sandberg et al., 2014) and Alzheimer's disease (Rother et al., 2022) acquire different properties during the progression of the disorders, but the existence of such emergent protein strains is still hypothetical. Here, Fan and colleagues present provocative, preliminary evidence that a particularly pathogenic (seeding active) form of aberrant ⍺-synuclein arises in the later stages of Parkinson's disease.
Cryo-EM has opened new vistas in the analysis of pathogenic protein assemblies, but critical caution is needed before the results can be comfortably integrated into molecular models of disease. The structural insights resulting from cryo-EM currently are tempered by technical challenges in achieving high-quality images from multiple samples and subjects, the numbers of which are still small. The limited sample sizes leave open many fundamental issues that could influence group comparisons; for instance, in the present study, the one subject representing the late Parkinson's disease phase was a woman; might there be sex differences in synuclein strain formation? Maybe not, but we need to know one way or the other. This late-PD case also differed from the mid-PD and pre-PD cases in the relatively early disease onset (50 years) and in the postmortem collection of CSF.
Sample selection-bias remains a thorny issue for Cryo-EM analyses in general—are there important variants of the pathogenic proteins that are unavailable for structural analysis (e.g., because they are bound to components of the tissue)? And how faithfully do samples from the CSF reflect the characteristics of aggregated proteins in the brain?
In using PMCA, does amplification of in vivo-derived material select for certain strains, or create new entities altogether? Fortunately, these are empirical questions that can be addressed as the field continues to advance. The findings of Fan et al. should draw needed experimental attention to the important issue of whether and how the properties of pathogenic proteins change over the course of neurodegenerative diseases.
National Institute on Aging
There is increasing evidence that there are aggregated forms of α-synuclein throughout many tissues that arise during disease evolution in Parkinson’s disease (PD) and related movement disorders, such as MSA. For example, several groups have now reliably documented the occurrence of proteinaceous material that can be amplified in a variety of biomatrices including CSF in many people with PD, much more so than in people without neurological diagnoses. In this context, the work from Fan, Sun, and colleagues is very interesting in that they show polymorphic structures of amplified synuclein with a suggestion of some change over time throughout the disease process. If replicated, this data might be helpful in designing ways to probe change in structure throughout the disease process that might provide a measure for disease progression, which has been greatly lacking for PD.
However, there are two substantive caveats that I think the reader should bear in mind. The first is that the true number of independent observations here is very low—in fact, the interesting late PD observation is based on n=1 CSF sample. If the presentation were focused on consistent similarities between cases, then I would not be overly concerned about this fact, but as there is a claim of difference I think it is important to note that it is not realistic to infer that the late PD sample is different from the others except as a chance event—or even a hidden confound.
As people with PD often have long-term illness, then acquisition of other late PD samples should not be too onerous. Additionally, I would be cautious about inferring pathogenicity of any recovered material from biological samples. While there is an attempt here to evaluate toxicity in a culture model, such acute experiments are hard to calibrate to the amount of material present in a given tissue in situ. As such, it is difficult to conclusively infer that amplifiable material represents pathogenicity, a protective response, or even an epiphenomenon of the disease process. If one is interested in developing a marker of the disease process then such considerations may be moot, but for interpretation of the current data I think these concerns are valid.
University of Texas Medical School at Houston
This is a very interesting article with some important potential caveats. The authors report different structures for α-synuclein (αSyn) amplified from CSF of patients at distinct stages of the disease, and they conclude that over disease progression αSyn aggregates change their structure. It is indeed an intriguing interpretation, which, if true, could have important implications for the understanding of the disease and the design of treatments.
One of the main problems I see with the experimental design is that they use CSF samples from different patients at distinct stages of disease progression. It is possible that different structures of αSyn aggregates may exist in different patients regardless of disease progression. This will be akin to different prion strains in distinct CJD cases, a finding that is well established. In order to conclude that the structure is changing over time, it would be necessary to use longitudinal samples collected from the same patient at different stages of the disease.
As commented by Scheres, Lövestam, and Goedert, it is possible that the structure of αSyn aggregates changes during in vitro amplification. In our experience, it is crucial to have a well-optimized protocol for amplification to rule out that some of the material formed in the reaction is not just coming from spontaneous aggregation. Interestingly, both in this paper, as well as the previous Lövestam article, the structures generated are very similar to spontaneous aggregates of αSyn. We have unpublished data (hope to publish soon) that the MSA structure amplified from CSF of patients is very similar to the one reported by Scheres and Goedert from the brain, when amplification conditions are well controlled.
The experience from the prion field in which these amplification techniques were initially developed, and much work has been done, is that depending on the specific protocol used you may maintain the biochemical, biological, infectious, and strain properties (see Castilla et al., 2005; Castilla et al., 2008) or you may obtain very different structures that are not infectious (e.g., using the RT-QuIC type of amplification assay). Up to now, it is not yet known if the atomic resolution structure of infectious prions amplified is the same as the one before amplification. We and others are working on this and data should come soon. As learnt from the prion field, it is likely that co-factors present in the brain may play an important role on faithful seeding. If this is also true for αSyn, it will be necessary to develop modified amplification protocols that contain these extra co-factors. This will also open an exciting new area of research in synucleinopathies and new potential targets for therapy.
References:
Castilla J, Saá P, Hetz C, Soto C. In vitro generation of infectious scrapie prions. Cell. 2005 Apr 22;121(2):195-206. PubMed.
Castilla J, Morales R, Saá P, Barria M, Gambetti P, Soto C. Cell-free propagation of prion strains. EMBO J. 2008 Oct 8;27(19):2557-66. Epub 2008 Sep 18 PubMed.
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Fan and colleagues report about conformational changes of α-synuclein (α-Syn) fibrils in cerebrospinal fluid (CSF) from different clinical stages of Parkinson’s disease (PD). Their findings feed into the discussion about urgently needed biomarkers for synucleinopathies. CSF from individuals with a synucleinopathy can induce concerted aggregation of recombinant, monomeric, α-Syn protein in Seed Amplification Assays (SAAs). It is assumed that such CSF samples contain α-Syn aggregates that act as seeds in this reaction (Soto et al., 2002; Fairfoul et al., 2016), however it is possible that molecules unrelated to α-Syn can contribute as well. Interestingly, SAAs using CSF and recombinant α-Syn have already been shown to be promising as a potential diagnostic tool for PD (Russo et al., 2021; Yoo et al., 2022; Poggiolini et al, 2022). Yet, so far, neither the structure of the seeds, nor of the SAA-derived recombinant α-Syn fibers, that are present as polymorphs, have been known.
In a labor-intense study, Fan et al. utilized cryogenic electron microscopy (cryo-EM) to visualize SAA-derived α-Syn polymorphs. Although it does not address the structure of the seeds that triggered the formation of the polymorphs in the SAA, this study describes for the first time CSF-induced polymorphic recombinant α-Syn structures. Several studies describe α-Syn polymorphs biochemically extracted from postmortem brain tissue (Schweighauser et al., 2020; Yang et al., 2022; Strohäker et al., 2019) or generated by incubating patient brain homogenates or brain-derived α-Syn filaments in an SAA (Lövestam et al., 2021: Burger et al., 2021). The CSF-triggered α-Syn polymorph structures described by Fan et al. resemble some of those previously reported α-Syn polymorphs.
Nevertheless, several technical aspects need to be considered for the interpretation of these results. First, preanalytical factors affect biophysical properties of α-Syn in CSF and introduce systematic variation in certain assays (Abdi et al., 2021). Second, the SAA always generates a plethora of different α-Syn polymorphs. The thermodynamically most stable polymorphs are enriched and thus become most likely to be detected by cryo-EM, while less stable ones continuously transform and escape cryo-EM analysis. Third, in vitro conditions such as pH, temperature, shaking, plastic surface of the reaction vial, purity of the recombinant α-Syn, composition of buffers, and nature of the biosample, influence which polymorphs become most stable (Close et al., 2018).
Another important question is how relevant are the CSF-triggered recombinant α-Syn polymorphs in relation to the underlying pathobiology of Lewy body disorders? Notably, in Lewy pathology, in situ correlative light and electron microscopy (CLEM) indicate that unstructured α-Syn co-localizes with lipids, membranes and damaged organelles rather than forming detectable polymorphic structures (Shahmoradian et al., 2019; May 2019 news). Furthermore, high-resolution microscopy studies suggest that different posttranslational modifications (PTM) of α-Syn orchestrate the formation of intracellular α-Syn pathology in the human brain (Moors et al., 2021). PTMs of α-Syn are abundant (Moors et al., 2022; Glasson et al., 2000; Mahul-Mellier et al., 2014) and they modify the solubility of α-Syn (Zhou et al., 2011; Bartels et al., 2014; Bluhm et al., 2021; Mishizen-Eberz et al., 2005; Levine et al., 2019). Therefore, α-Syn PTMs potentially influence the formation of polymorphs in cells or in an SAA (Guerrero-Ferreira et al., 2018; Guerrero-Ferreira et al., 2019; Schweighauser et al., 2020). Hence, one could use α-Syn with different PTMs as substrate in SAAs and define the structures of the resulting α-Syn polymorphs and their relationship to in situ structures.
The study by Fan et al. suggests that α-Syn polymorphism observed in the SAA changes with the progression of the disease. Thus, one could hypothesize that there are different amounts of α-Syn PTMs present during disease progression that affect the generation of α-Syn-related seeds in the CSF. Since cryo-EM exclusively captures the well-represented, repetitive, and rigidly structured motifs of, in this case, synthetically amplified, rare, and unknown polymorphic traces, it would be important to understand the biophysical and pathological drivers that modulate polymorphism in vivo.
Finally, in order to establish SAA as robust biomarker assay, it would help the field if studies directly comparing results between laboratories regarding the generation of α-Syn polymorphs derived from SAAs were performed, as is standard practice for immunoassays (Mollenhauer et al., 2018). For instance, studies exploring the value of α-Syn SAA as a diagnostic tool, as reported by Russo and colleagues, could be expanded by a cryo-EM analysis (Russo et al., 2021).
As done in the Alzheimer’s field (Angioni et al., 2022; Sep 2021 news), collaborations across academic and industrial teams might accelerate these efforts for PD and other synucleinopathies and could help expand the number of samples tested. It will be important to incorporate age and gender matching of controls, as well as understanding the impact of sample storage time and conditions. Such studies will be critical to detailed understanding of how α-Syn polymorphs generated using CSF samples relate to disease stage and α-Syn polymorphs in the nervous system.
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