Abstract
Amyloid aggregation, which disrupts protein homeostasis, is a common pathological event occurring in human neurodegenerative diseases (NDs). Numerous evidences have shown that the structural diversity, so-called polymorphism, is decisive to the amyloid pathology and is closely associated with the onset, progression, and phenotype of ND. But how could one protein form so many stable structures? Recently, atomic structural evidence has been rapidly mounting to depict the involvement of chemical modifications in the amyloid fibril formation. In this Perspective, we aim to present a hierarchical regulation of chemical modifications including covalent post-translational modifications (PTMs) and noncovalent cofactor binding in governing the polymorphic amyloid formation, based mainly on the latest α-synuclein and Tau fibril structures. We hope to emphasize the determinant role of chemical modifications in amyloid assembly and pathology and to evoke chemical biological approaches to lead the fundamental and therapeutic research on protein amyloid state and the associated NDs.
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References
Lee, V. M., Goedert, M. & Trojanowski, J. Q. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121–1159 (2001).
Soto, C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat. Rev. Neurosci. 4, 49–60 (2003).
Lin, M. T. & Beal, M. F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795 (2006).
Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).
Irwin, D. J., Lee, V. M. & Trojanowski, J. Q. Parkinson’s disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat. Rev. Neurosci. 14, 626–636 (2013).
Nussbaum, R. L. & Ellis, C. E. Alzheimer’s disease and Parkinson’s disease. N. Engl. J. Med. 348, 1356–1364 (2003).
Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047 (1997).
Mayeux, R. et al. Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer’s disease. Neurology 45, 555–557 (1995).
Eimer, W. A. et al. Alzheimer’s disease-associated β-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 100, 1527–1532 (2018).
Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480.e12 (2016).
Zhang, W. et al. Novel tau filament fold in corticobasal degeneration. Nature 580, 283–287 (2020).
Schweighauser, M. et al. Structures of α-synuclein filaments from multiple system atrophy. Nature 585, 464–469 (2020). This study reports the pathological fibril structure of α-synuclein derived from patients of multiple system atrophy.
Eisenberg, D. & Jucker, M. The amyloid state of proteins in human diseases. Cell 148, 1188–1203 (2012).
Kam, T. I. et al. Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease. Science 362, eaat8407 (2018). This article demonstrates the important role of poly(ADP-ribose) as an endogenous cofactor of α-synuclein to regulate its aggregation and pathology in cells.
Jucker, M. & Walker, L. C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45–51 (2013).
Gambetti, P. et al. Molecular biology and pathology of prion strains in sporadic human prion diseases. Acta Neuropathol. 121, 79–90 (2011).
Meda, L. et al. Activation of microglial cells by β-amyloid protein and interferon-gamma. Nature 374, 647–650 (1995).
Olzscha, H. et al. Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell 144, 67–78 (2011).
Ruan, L. et al. Cytosolic proteostasis through importing of misfolded proteins into mitochondria. Nature 543, 443–446 (2017).
Falcon, B. et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568, 420–423 (2019).
Peng, C. et al. Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies. Nature 557, 558–563 (2018). This article highlights that different cellular environments may lead to the formation of α-synuclein fibrils with distinct structures and neuropathologies.
Falcon, B. et al. Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature 561, 137–140 (2018).
Qiang, W., Yau, W. M., Lu, J. X., Collinge, J. & Tycko, R. Structural variation in amyloid-β fibrils from Alzheimer’s disease clinical subtypes. Nature 541, 217–221 (2017).
Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease.Nature 547, 185–190 (2017). This paper reports the atomic structure of pathological fibrils directly extracted from the brain of a patient with AD.
Peelaerts, W. et al. α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522, 340–344 (2015). This study highlights the diverse structures and pathologies of different strains of α-synuclein fibrils.
Dobson, C. M., Knowles, T. P. J. & Vendruscolo, M. The Amyloid phenomenon and its significance in biology and medicine. Cold Spring Harb. Perspect. Biol. 12, a033878 (2020).
Nelson, R. et al. Structure of the cross-β spine of amyloid-like fibrils. Nature 435, 773–778 (2005).
Sawaya, M. R. et al. Atomic structures of amyloid cross-β spines reveal varied steric zippers. Nature 447, 453–457 (2007).
Zhang, W. et al. Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases. eLife 8, e43584 (2019).
Arakhamia, T. et al. Posttranslational modifications mediate the structural diversity of tauopathy strains. Cell 180, 633–644.e12 (2020). This article highlights the important role of post-translational modifications in determining the structures of Tau fibrils in different types of tauopathies.
Zhao, K. et al. Parkinson’s disease associated mutation E46K of α-synuclein triggers the formation of a distinct fibril structure. Nat. Commun. 11, 2643 (2020).
Ni, X., McGlinchey, R. P., Jiang, J. & Lee, J. C. Structural Insights into α-synuclein fibril polymorphism: effects of Parkinson’s disease-related C-terminal truncations. J. Mol. Biol. 431, 3913–3919 (2019).
Li, Y. et al. Amyloid fibril structure of α-synuclein determined by cryo-electron microscopy. Cell Res. 28, 897–903 (2018).
Li, B. et al. Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel. Nat. Commun. 9, 3609 (2018).
Guerrero-Ferreira, R. et al. Cryo-EM structure of α-synuclein fibrils. eLife 7, e36402 (2018).
Kollmer, M. et al. Cryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer’s brain tissue. Nat. Commun. 10, 4760 (2019).
Gremer, L. et al. Fibril structure of amyloid-β(1-42) by cryo-electron microscopy. Science 358, 116–119 (2017).
Wang, L. Q. et al. Cryo-EM structure of an amyloid fibril formed by full-length human prion protein. Nat. Struct. Mol. Biol. 27, 598–602 (2020). This study shows non-proteinaceous molecules that mediate the formation of fibrils of full-length human prions.
Glynn, C. et al. Cryo-EM structure of a human prion fibril with a hydrophobic, protease-resistant core. Nat. Struct. Mol. Biol. 27, 417–423 (2020).
Zhao, K. et al. Parkinson’s disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM. Proc. Natl. Acad. Sci. USA 117, 20305–20315 (2020). This study reveals the structural basis of how a disease-associated phosphorylation induces the formation of a new fibril structure of α-synuclein with enhanced stability and neurotoxicity.
Friedrich, N. & Kekule, A. Zur amyloidfrage. Virchows Arch. Pathol. Anat. Physiol. 16, 50–65 (1859).
Li, D. & Liu, C. Structural diversity of amyloid fibrils and advances in their structure determination. Biochemistry 59, 639–646 (2020).
Fitzpatrick, A. W. & Saibil, H. R. Cryo-EM of amyloid fibrils and cellular aggregates. Curr. Opin. Struct. Biol. 58, 34–42 (2019).
Iadanza, M. G., Jackson, M. P., Hewitt, E. W., Ranson, N. A. & Radford, S. E. A new era for understanding amyloid structures and disease. Nat. Rev. Mol. Cell Biol. 19, 755–773 (2018).
Guerrero-Ferreira, R., Kovacik, L., Ni, D. & Stahlberg, H. New insights on the structure of α-synuclein fibrils using cryo-electron microscopy. Curr. Opin. Neurobiol. 61, 89–95 (2020).
Goedert, M., Falcon, B., Zhang, W., Ghetti, B. & Scheres, S. H. W. Distinct conformers of assembled tau in Alzheimer’s and Pick’s diseases. Cold Spring Harb. Symp. Quant. Biol. 83, 163–171 (2018).
Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982).
Walker, L. C. Proteopathic strains and the heterogeneity of neurodegenerative diseases. Annu. Rev. Genet. 50, 329–346 (2016).
Sanders, D. W., Kaufman, S. K., Holmes, B. B. & Diamond, M. I. Prions and protein assemblies that convey biological information in health and disease. Neuron 89, 433–448 (2016).
Safar, J. et al. Eight prion strains have PrP(Sc) molecules with different conformations. Nat. Med. 4, 1157–1165 (1998).
Collinge, J. & Clarke, A. R. A general model of prion strains and their pathogenicity. Science 318, 930–936 (2007).
Prusiner, S. B. Biology and genetics of prions causing neurodegeneration. Annu. Rev. Genet. 47, 601–623 (2013).
Walker, L. C. & Jucker, M. Neurodegenerative diseases: expanding the prion concept. Annu. Rev. Neurosci. 38, 87–103 (2015).
Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).
Taniguchi-Watanabe, S. et al. Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau. Acta Neuropathol. 131, 267–280 (2016).
Boluda, S. et al. Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. Acta Neuropathol. 129, 221–237 (2015).
Nekooki-Machida, Y. et al. Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity. Proc. Natl. Acad. Sci. USA 106, 9679–9684 (2009).
Arnold, S. E. et al. Comparative survey of the topographical distribution of signature molecular lesions in major neurodegenerative diseases. J. Comp. Neurol. 521, 4339–4355 (2013).
Brettschneider, J. et al. Converging patterns of α-synuclein pathology in multiple system atrophy. J. Neuropathol. Exp. Neurol. 77, 1005–1016 (2018).
Trojanowski, J. Q., Revesz, T. & Neuropathology Working Group on MSA. Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol. Appl. Neurobiol. 33, 615–620 (2007).
Spillantini, M. G. et al. α-synuclein in Lewy bodies. Nature 388, 839–840 (1997).
He, Z. et al. Transmission of tauopathy strains is independent of their isoform composition. Nat. Commun. 11, 7 (2020).
Guerrero-Ferreira, R. et al. Two new polymorphic structures of human full-length α-synuclein fibrils solved by cryo-electron microscopy. eLife 8, e48907 (2019).
Tuttle, M. D. et al. Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein. Nat. Struct. Mol. Biol. 23, 409–415 (2016).
Paravastu, A. K., Leapman, R. D., Yau, W. M. & Tycko, R. Molecular structural basis for polymorphism in Alzheimer’s β-amyloid fibrils. Proc. Natl. Acad. Sci. USA 105, 18349–18354 (2008).
De Franceschi, G. et al. Structural and morphological characterization of aggregated species of α-synuclein induced by docosahexaenoic acid. J. Biol. Chem. 286, 22262–22274 (2011).
Miura, T., Suzuki, K., Kohata, N. & Takeuchi, H. Metal binding modes of Alzheimer’s amyloid β-peptide in insoluble aggregates and soluble complexes. Biochemistry 39, 7024–7031 (2000).
Porta, S. et al. Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo. Nat. Commun. 9, 4220 (2018).
Peng, C., Trojanowski, J. Q. & Lee, V. M. Protein transmission in neurodegenerative disease. Nat. Rev. Neurol. 16, 199–212 (2020).
Pedersen, J. S. & Otzen, D. E. Amyloid-a state in many guises: survival of the fittest fibril fold. Protein Sci. 17, 2–10 (2008).
Levine, P. M. et al. α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson’s disease. Proc. Natl. Acad. Sci. USA 116, 1511–1519 (2019). This study highlights that GlcNAcylation at different sites of α-synuclein exhibits distinctive effects on α-synuclein aggregation and toxicity.
Brahmachari, S. et al. Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration. J. Clin. Invest. 126, 2970–2988 (2016).
Morris, M. et al. Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat. Neurosci. 18, 1183–1189 (2015).
Mahul-Mellier, A. L. et al. c-Abl phosphorylates α-synuclein and regulates its degradation: implication for α-synuclein clearance and contribution to the pathogenesis of Parkinson’s disease. Hum. Mol. Genet. 23, 2858–2879 (2014).
Tenreiro, S., Eckermann, K. & Outeiro, T. F. Protein phosphorylation in neurodegeneration: friend or foe? Front. Mol. Neurosci. 7, 42 (2014).
Hu, Z. W. et al. Molecular structure of an N-terminal phosphorylated β-amyloid fibril. Proc. Natl. Acad. Sci. USA 116, 11253–11258 (2019).
Cohlberg, J. A., Li, J., Uversky, V. N. & Fink, A. L. Heparin and other glycosaminoglycans stimulate the formation of amyloid fibrils from α-synuclein in vitro. Biochemistry 41, 1502–1511 (2002).
Galvagnion, C. et al. Chemical properties of lipids strongly affect the kinetics of the membrane-induced aggregation of α-synuclein. Proc. Natl. Acad. Sci. USA 113, 7065–7070 (2016).
Wilson, D. M. & Binder, L. I. Free fatty acids stimulate the polymerization of tau and amyloid beta peptides. In vitro evidence for a common effector of pathogenesis in Alzheimer’s disease. Am. J. Pathol. 150, 2181–2195 (1997).
Kampers, T., Friedhoff, P., Biernat, J., Mandelkow, E. M. & Mandelkow, E. RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett. 399, 344–349 (1996).
Dikiy, I. et al. Semisynthetic and in vitro phosphorylation of alpha-synuclein at Y39 promotes functional partly helical membrane-bound states resembling those induced by PD mutations. ACS Chem. Biol. 11, 2428–2437 (2016).
Nussbaum, J. M. et al. Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β. Nature 485, 651–655 (2012). This study reports that pyroglutamylation of amyloid-β plays an important role in mediating its Tau-dependent pathology.
Kummer, M. P. et al. Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation. Neuron 71, 833–844 (2011).
Goedert, M. et al. Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383, 550–553 (1996).
Suzuki, K. et al. Neurofibrillary tangles in Niemann-Pick disease type C. Acta Neuropathol. 89, 227–238 (1995).
Mandelkow, E. M. & Mandelkow, E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb. Perspect. Med. 2, a006247 (2012).
Carlomagno, Y. et al. An acetylation-phosphorylation switch that regulates tau aggregation propensity and function. J. Biol. Chem. 292, 15277–15286 (2017).
Seidler, P. et al. CryoEM reveals how the small molecule EGCG binds to Alzheimer’s brain-derived tau fibrils and initiates fibril disaggregation. Preprint at bioRxiv https://doi.org/10.1101/2020.05.29.124537 (2020).
Hartrampf, N. et al. Synthesis of proteins by automated flow chemistry. Science 368, 980–987 (2020).
Acknowledgements
This work was supported by the Major State Basic Research Development Program (2016YFA0501902 to C.L.), the National Natural Science Foundation (NSF) of China (91853113 and 31872716 to C.L. and D.L.), the Science and Technology Commission of Shanghai Municipality (18JC1420500 to C.L.), “Eastern Scholar” project supported by Shanghai Municipal Education Commission (D.L.), and the Shanghai Municipal Science and Technology Major Project (2019SHZDZX02 to C.L.).
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Li, D., Liu, C. Hierarchical chemical determination of amyloid polymorphs in neurodegenerative disease. Nat Chem Biol 17, 237–245 (2021). https://doi.org/10.1038/s41589-020-00708-z
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DOI: https://doi.org/10.1038/s41589-020-00708-z
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