Meade RM, Williams RJ, Mason JM.
A series of helical α-synuclein fibril polymorphs are populated in the presence of lipid vesicles.
NPJ Parkinsons Dis. 2020;6:17. Epub 2020 Aug 19
PubMed.
Ulf Dettmer Harvard Medical School, Brigham and Women’s Hospital
Posted:
Interaction with membranes represents a crucial aspect of the physiology of α-synuclein (αSyn). As far as pathology is concerned, excess vesicle interaction has been proposed to trigger αSyn aggregation via primary nucleation (Galvagnion et al., 2015). In this recent paper, Jody Mason’s group described the transmission electron microscopy (TEM) low-resolution structure of αSyn fibrils that formed upon aggregation of recombinant αSyn in the presence of synaptic vesicle-mimicking small unilamellar vesicles (SUVs) formed by dimyristoylphosphatidylserine (DMPS). Although fibrils formed under such conditions have been studied with atomic resolution by solid-state NMR (ssNMR) before (Galvagnion et al., 2019), here Mede et al. allow for additional incubation time under quiescent conditions and find that this approach promotes the formation of fibrils with rather different assemblies than those described before. These novel polymorphs adopt a helical arrangement with varying degrees of compaction and compression. Such supramolecular helices of aggregated αSyn must not be confused with α-helical secondary structure of single αSyn molecules.
The presented approach could be interesting for studies of in vitro αSyn aggregation and opens the door to a multitude of experiments that could further validate the relevance of the described large polymorphs. For example, it would be interesting to determine if the different familial PD-related missense mutations in αSyn promote the formation of different polymorphs—they certainly do in the “early” fibrils as determined by cryo-EM (Boyer et al., 2020; Zhao et al., 2020). Also, does the SUV composition have a role in the form and distribution of such aggregates? Is the circular dichroism-detected secondary structure of the polymorphs shifting throughout the incubation period (i.e., is the β-sheet content the same in “early” and “incubated” fibrils)? Further, does quiescent incubation of αSyn fibrils formed in the absence of lipids eventually yield large aggregates such as the ones described here? And lastly, will detailed analysis of PD brain lesions provide any evidence of similar supramolecular αSyn helices?
While Meade et al. undoubtedly present intriguing findings, more information will be needed to establish the relevance of the polymorphs in the dysfunction and aggregation of αSyn in disease.
References:
Boyer DR, Li B, Sun C, Fan W, Zhou K, Hughes MP, Sawaya MR, Jiang L, Eisenberg DS.
The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure.
Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3592-3602. Epub 2020 Feb 3
PubMed.
Galvagnion C, Buell AK, Meisl G, Michaels TC, Vendruscolo M, Knowles TP, Dobson CM.
Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation.
Nat Chem Biol. 2015 Mar;11(3):229-34. Epub 2015 Feb 2
PubMed.
Galvagnion C, Topgaard D, Makasewicz K, Buell AK, Linse S, Sparr E, Dobson CM.
Lipid Dynamics and Phase Transition within α-Synuclein Amyloid Fibrils.
J Phys Chem Lett. 2019 Dec 19;10(24):7872-7877. Epub 2019 Dec 6
PubMed.
Zhao K, Li Y, Liu Z, Long H, Zhao C, Luo F, Sun Y, Tao Y, Su XD, Li D, Li X, Liu C.
Parkinson's disease associated mutation E46K of α-synuclein triggers the formation of a distinct fibril structure.
Nat Commun. 2020 May 26;11(1):2643.
PubMed.
Comments
Harvard Medical School, Brigham and Women's Hospital
Harvard Medical School, Brigham and Women’s Hospital
Interaction with membranes represents a crucial aspect of the physiology of α-synuclein (αSyn). As far as pathology is concerned, excess vesicle interaction has been proposed to trigger αSyn aggregation via primary nucleation (Galvagnion et al., 2015). In this recent paper, Jody Mason’s group described the transmission electron microscopy (TEM) low-resolution structure of αSyn fibrils that formed upon aggregation of recombinant αSyn in the presence of synaptic vesicle-mimicking small unilamellar vesicles (SUVs) formed by dimyristoylphosphatidylserine (DMPS). Although fibrils formed under such conditions have been studied with atomic resolution by solid-state NMR (ssNMR) before (Galvagnion et al., 2019), here Mede et al. allow for additional incubation time under quiescent conditions and find that this approach promotes the formation of fibrils with rather different assemblies than those described before. These novel polymorphs adopt a helical arrangement with varying degrees of compaction and compression. Such supramolecular helices of aggregated αSyn must not be confused with α-helical secondary structure of single αSyn molecules.
The presented approach could be interesting for studies of in vitro αSyn aggregation and opens the door to a multitude of experiments that could further validate the relevance of the described large polymorphs. For example, it would be interesting to determine if the different familial PD-related missense mutations in αSyn promote the formation of different polymorphs—they certainly do in the “early” fibrils as determined by cryo-EM (Boyer et al., 2020; Zhao et al., 2020). Also, does the SUV composition have a role in the form and distribution of such aggregates? Is the circular dichroism-detected secondary structure of the polymorphs shifting throughout the incubation period (i.e., is the β-sheet content the same in “early” and “incubated” fibrils)? Further, does quiescent incubation of αSyn fibrils formed in the absence of lipids eventually yield large aggregates such as the ones described here? And lastly, will detailed analysis of PD brain lesions provide any evidence of similar supramolecular αSyn helices?
While Meade et al. undoubtedly present intriguing findings, more information will be needed to establish the relevance of the polymorphs in the dysfunction and aggregation of αSyn in disease.
References:
Boyer DR, Li B, Sun C, Fan W, Zhou K, Hughes MP, Sawaya MR, Jiang L, Eisenberg DS. The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure. Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3592-3602. Epub 2020 Feb 3 PubMed.
Galvagnion C, Buell AK, Meisl G, Michaels TC, Vendruscolo M, Knowles TP, Dobson CM. Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation. Nat Chem Biol. 2015 Mar;11(3):229-34. Epub 2015 Feb 2 PubMed.
Galvagnion C, Topgaard D, Makasewicz K, Buell AK, Linse S, Sparr E, Dobson CM. Lipid Dynamics and Phase Transition within α-Synuclein Amyloid Fibrils. J Phys Chem Lett. 2019 Dec 19;10(24):7872-7877. Epub 2019 Dec 6 PubMed.
Zhao K, Li Y, Liu Z, Long H, Zhao C, Luo F, Sun Y, Tao Y, Su XD, Li D, Li X, Liu C. Parkinson's disease associated mutation E46K of α-synuclein triggers the formation of a distinct fibril structure. Nat Commun. 2020 May 26;11(1):2643. PubMed.
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