Joerg Hoernschmeyer, and Johannes Erny at Roche for 648 their technical support to clone, express, purify and characterize the different forms of ?-Syn ,
Lubomir Kovacik and Ariane Fecteau-Lefebvre for support in cryo-EM ,
, Calculations were performed using the high-performance computing (HPC) infrastructure 651 administered by the scientific computing center at the University of Basel (sciCORE
, The Novo Nordisk Foundation Center for Protein Research is 653 supported financially by the Novo Nordisk Foundation (NNF14CC0001). N.M.I.T. is a 654 member of the Integrative Structural Biology Cluster (ISBUC) at the University of, p.655
and 660 R.M. received funding from the European Union's Horizon 2020 research and innovation 661 programme under grant agreement No. 116060 (IMPRiND), the Swiss State Secretariat for 662 Education, This work was in part supported by the Synapsis Foundation Switzerland, the 656 Heidi-Seiler Stiftung Foundation, and the Swiss National Science Foundation (grants 657 CRSII3_154461 and CRSII5_177195 and 20020_178792), and the French ANR, p.663 ,
, The Fondation Simone et Cino Del Duca of the Institut de France and the EC 665 Joint Program on Neurodegenerative Diseases (TransPathND, vol.664
New tool: 777 phenix_real_space_refine, Comp. Crystal. Newsletter, vol.4, issue.2, pp.43-44, 2013. ,
, , p.779
, , p.780
Alpha-synuclein p.H50Q, a novel pathogenic 781 mutation for Parkinson's disease, Mov Disord, vol.28, issue.6, pp.811-813, 2013. ,
Reducing C-terminal truncation mitigates 784 synucleinopathy and neurodegeneration in a transgenic model of multiple system 785 atrophy, Proceedings of the National Academy of Sciences, vol.113, issue.34, pp.9593-9598, 2016. ,
, , p.787
Focus: The interface between data collection and data processing 788 in cryo-EM, J Struct Biol, vol.198, issue.2, pp.124-133, 2017. ,
, , p.790
Structural and functional 791 characterization of two alpha-synuclein strains, Nat Commun, 2013. ,
The presence 793 of an air-water interface affects formation and elongation of alpha-Synuclein fibrils, J 794 Am Chem Soc, vol.136, issue.7, pp.2866-2875, 2014. ,
, , p.796
, , p.797
Alpha-synuclein locus duplication as a 798 cause of familial Parkinson's disease, Lancet, vol.364, issue.9440, pp.1167-1169, 2004. ,
, , p.800
Physical basis of amyloid fibril 801 polymorphism, Nat Commun, vol.9, issue.1, p.699, 2018. ,
Structural 803 intermediates during alpha-synuclein fibrillogenesis on phospholipid vesicles, J Am, vol.804, 2012. ,
, Chem Soc, vol.134, issue.11, pp.5090-5099
, , p.806
Structured regions of 807 alpha-synuclein fibrils include the early-onset Parkinson's disease mutation sites, J 808 Mol Biol, vol.411, issue.4, pp.881-895, 2011. ,
Accelerated in vitro fibril formation by a 810 mutant alpha-synuclein linked to early-onset Parkinson disease, Nature medicine, vol.811, issue.11, pp.1318-1320, 1998. ,
Characterisation of isolated alpha-synuclein 813 filaments from substantia nigra of Parkinson's disease brain, Neuroscience letters, vol.814, issue.2, pp.128-130, 2000. ,
Synthetic filaments 816 assembled from C-terminally truncated alpha-synuclein, FEBS Lett, vol.436, issue.3, pp.309-312, 1998. ,
Proton 818 assisted recoupling and protein structure determination, J Chem Phys, vol.129, issue.24, p.245101, 2008. ,
, , p.822
Loss of native alpha-synuclein multimerization by strategically mutating its amphipathic helix causes abnormal vesicle interactions in neuronal cells, 2017. ,
, Hum Mol Genet, vol.26, issue.18, pp.3466-3481
Calpain-cleavage of alpha-827 synuclein: connecting proteolytic processing to disease-linked aggregation, Am J 828 Pathol, vol.170, issue.5, pp.1725-1738, 2007. ,
, , p.830
Aggregates from mutant and wild-type alpha-synuclein 831 proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells 832 by formation of beta-sheet and amyloid-like filaments, FEBS Lett, vol.440, issue.1-2, pp.71-75, 1998. ,
Coot: model-building tools for molecular graphics, Acta 834 Crystallogr D Biol Crystallogr, vol.60, pp.2126-2132, 2004. ,
Structures of filaments from 837 Pick's disease reveal a novel tau protein fold, Nature, vol.561, issue.7721, pp.137-140, 2018. ,
,
Novel tau filament fold 840 in chronic traumatic encephalopathy encloses hydrophobic molecules, Nature, vol.841, issue.7752, pp.420-423, 2019. ,
Amyloid fibril polymorphism: a challenge for molecular imaging and 844 therapy, J Intern Med, vol.283, issue.3, pp.218-237, 2018. ,
, , p.846
Cryo-EM structures 847 of tau filaments from Alzheimer's disease, Nature, vol.547, issue.7662, pp.185-190, 2017. ,
, , p.849
Mutations associated with familial Parkinson's disease alter the 850 initiation and amplification steps of alpha-synuclein aggregation, Proc Natl Acad Sci, vol.851, issue.37, pp.10328-10333, 2016. ,
Update on 853 novel familial forms of Parkinson's disease and multiple system atrophy, 2014. ,
, Parkinsonism & related disorders, vol.20, pp.1-29
Solid-856 state NMR sequential assignments of alpha-synuclein, Biomol NMR Assign, vol.6, issue.1, pp.51-857, 2012. ,
Yet 859 another polymorph of alpha-synuclein: solid-state sequential assignments, NMR Assign, vol.860, issue.2, pp.395-404, 2014. ,
Unlike 862 twins: an NMR comparison of two alpha-synuclein polymorphs featuring different 863 toxicity, PLoS One, vol.9, issue.3, p.90659, 2014. ,
The synucleins, Genome Biol, vol.3, issue.1, p.3002, 2002. ,
Characterization of a novel protein 866 regulated during the critical period for song learning in the zebra finch, Neuron, vol.15, issue.2, pp.361-372, 1995. ,
PA700, the regulatory complex of the 26S 869 proteasome, interferes with alpha-synuclein assembly, FEBS J, vol.272, issue.16, pp.4023-4033, 2005. ,
A hydrophobic stretch of 12 871 amino acid residues in the middle of alpha-synuclein is essential for filament 872 assembly, J Biol Chem, vol.276, issue.4, pp.2380-2386, 2001. ,
, , vol.874
Fibril 875 structure of amyloid-beta(1-42) by cryo-electron microscopy, Science, vol.358, issue.6359, pp.116-119, 2017. ,
Cryo-EM structure of alpha-synuclein fibrils, Elife, vol.879, issue.e36402, p.7, 2018. ,
, , 1998.
, Human recombinant NACP/alpha-synuclein is aggregated and fibrillated in vitro: 882 relevance for Lewy body disease, Brain Res, vol.799, issue.2, pp.301-306
Helical reconstruction in RELION, J Struct Biol, vol.198, issue.3, pp.163-884, 2017. ,
Molecular-886 level secondary structure, polymorphism, and dynamics of full-length alpha-synuclein 887 fibrils studied by solid-state NMR, Proc Natl Acad Sci U S A, vol.102, issue.44, pp.15871-15876, 2005. ,
A new method for purification of 889 recombinant human alpha-synuclein in Escherichia coli, Protein Expr Purif, vol.42, issue.1, pp.173-177, 2005. ,
Causal relation between alpha-synuclein gene duplication and 893 familial Parkinson's disease, Lancet, vol.364, issue.9440, pp.1169-1171, 2004. ,
, , p.895
Purification and characterization of Lewy bodies from the brains of 896 patients with diffuse Lewy body disease, Am J Pathol, vol.148, issue.5, pp.1517-1529, 1996. ,
Identification of two distinct synucleins from 898 human brain, FEBS Lett, vol.345, issue.1, pp.27-32, 1994. ,
Targeted Amino-Terminal 900 Acetylation of Recombinant Proteins in E. coli, PLOS ONE, vol.5, issue.12, p.15801, 2010. ,
Ala30Pro mutation in the gene encoding alpha-903 synuclein in Parkinson's disease, Nat Genet, vol.18, issue.2, pp.106-108, 1998. ,
,
G51D alpha-synuclein mutation causes a novel 907 parkinsonian-pyramidal syndrome, Annals of neurology, vol.73, issue.4, pp.459-471, 2013. ,
Proton assisted insensitive nuclei 909 cross polarization, J Am Chem Soc, vol.129, issue.4, pp.728-729, 2007. ,
, , p.911
Imaging of post-mortem human brain 912 tissue using electron and X-ray microscopy, Current opinion in structural biology, vol.913, pp.58138-148, 2019. ,
, , p.915
Cryo-EM of full-916 length ?-synuclein reveals fibril polymorphs with a common structural kernel, Nature, 2018. ,
Structural transformation and 919 aggregation of human alpha-synuclein in trifluoroethanol: non-amyloid component 920 sequence is essential and beta-sheet formation is prerequisite to aggregation, 2002. ,
, Biopolymers, vol.64, issue.4, pp.221-226
Aggregation promoting C-terminal 924 truncation of alpha-synuclein is a normal cellular process and is enhanced by the 925 familial Parkinson's disease-linked mutations, Proc Natl Acad Sci U S A, vol.102, issue.6, pp.926-2162, 2005. ,
928 Localization of alpha-synuclein to mitochondria within midbrain of mice, 2007. ,
, Neuroreport, vol.18, issue.15, pp.1543-1546
, , 2018.
, Amyloid fibril structure of ?-synuclein determined by cryo-electron microscopy, Research, vol.932, issue.9, pp.897-903
A 934 precipitating role for truncated alpha-synuclein and the proteasome in alpha-synuclein 935 aggregation: implications for pathogenesis of Parkinson disease, J Biol Chem, vol.936, issue.24, pp.22670-22678, 2005. ,
, , p.938
Exogenous alpha-synuclein fibrils seed the formation of Lewy 939 body-like intracellular inclusions in cultured cells, Proc Natl Acad Sci U S A, vol.106, issue.47, pp.940-20051, 2009. ,
Structural comparison of mouse and human alpha-synuclein amyloid fibrils 943 by solid-state NMR, J Mol Biol, vol.420, issue.1-2, pp.99-111, 2012. ,
, , p.945
, , p.947
The making of a Lewy body: the role of alpha-948 synuclein post-fibrillization modifications in regulating the formation and the 949 maturation of pathological inclusions, p.500058, 2019. ,
Automated electron microscope tomography using robust 951 prediction of specimen movements, J Struct Biol, vol.152, issue.1, pp.36-51, 2005. ,
Cysteine misincorporation in bacterially expressed human alpha-synuclein, 2006. ,
, FEBS Lett, vol.580, issue.7, pp.1775-1779
, , p.956
Parkinson disease 957 mutant E46K enhances alpha-synuclein phosphorylation in mammalian cell lines, in 958 yeast, and in vivo, J Biol Chem, vol.290, issue.15, pp.9412-9427, 2015. ,
The structure of fibrils from 'misfolded' proteins. Current 960 opinion in structural biology, pp.3043-3092, 2015. ,
URL : https://hal.archives-ouvertes.fr/hal-01147003
, , p.962
, , p.964
Detailed structural orchestration of Lewy 965 pathology in Parkinson's disease as revealed by 3D multicolor STED microscopy, vol.966, p.470476, 2018. ,
Prion-like acceleration of a synucleinopathy in a transgenic 969 mouse model, Neurobiol Aging, vol.33, issue.9, pp.2225-2228, 2012. ,
Ubiquitination of alpha-synuclein, 2005. ,
, Biochemistry, vol.44, issue.1, pp.361-368
Chapter 7 -Role of post-translational 973 modifications in modulating the structure, function and toxicity of ?-synuclein: 974 Implications for Parkinson's disease pathogenesis and therapies, pp.115-145, 2010. ,
, Progress in Brain Research
Novel alpha-synuclein mutation A53E 978 associated with atypical multiple system atrophy and Parkinson's disease-type 979 pathology, Neurobiol Aging, vol.35, issue.9, pp.2180-2181, 2014. ,
alpha-Synuclein strains cause 982 distinct synucleinopathies after local and systemic administration, Nature, vol.522, issue.7556, pp.340-344, 2015. ,
, , p.985
Cellular 986 milieu imparts distinct pathological alpha-synuclein strains in alpha-987 synucleinopathies, Nature, vol.557, issue.7706, pp.558-563, 2018. ,
Interaction of human alpha-989 Synuclein and Parkinson's disease variants with phospholipids. Structural analysis 990 using site-directed mutagenesis, J Biol Chem, vol.275, issue.44, pp.34393-34398, 2000. ,
, , p.992
UCSF Chimera--a visualization system for exploratory research 993 and analysis, J Comput Chem, vol.25, issue.13, pp.1605-1612, 2004. ,
, , p.995
, , p.996
Mutation in the alpha-998 synuclein gene identified in families with Parkinson's disease, Science, vol.276, issue.5321, pp.999-2045, 1997. ,
Can Interactions Between ?-Synuclein, p.1001, 2018. ,
, Dopamine and Calcium Explain Selective Neurodegeneration in Parkinson's Disease? 1002 Frontiers in Neuroscience 12161
Critical role of truncated alpha-1004 synuclein and aggregates in Parkinson's disease and incidental Lewy body disease, 2012. ,
, Brain Pathol, vol.22, issue.6, pp.811-825
, , p.1007
A novel alpha-synuclein missense mutation in 1008 Parkinson disease, Neurology, vol.80, issue.11, pp.1062-1064, 2013. ,
The Three-Dimensional Structures of Amyloids. Cold Spring Harb Perspect, Biol, vol.9, issue.2, p.23572, 1010. ,
, , p.1012
, , p.1013
Structure of the toxic core of alpha-synuclein 1015 from invisible crystals, Nature, vol.525, issue.7570, pp.486-490, 2015. ,
RELION: implementation of a Bayesian approach to cryo-EM structure 1017 determination, Journal of Structural Biology, vol.180, issue.3, pp.519-530, 2012. ,
, , p.1019
Atomic-resolution three-1020 dimensional structure of amyloid beta fibrils bearing the Osaka mutation, Angew 1021 Chem Int Ed Engl, vol.54, issue.1, pp.331-335, 2015. ,
, , p.1023
, , p.1024
,
, , p.1027
, , 2019.
, Lewy pathology in Parkinson's disease consists of crowded organelles and lipid 1029 membranes, Nature neuroscience, vol.22, issue.7, pp.1099-1109
, , p.1031
, , p.1032
, , p.1033
alpha-Synuclein locus triplication 1034 causes Parkinson's disease, Science, vol.302, issue.5646, p.841, 2003. ,
?-Synuclein 1036 in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with 1037 Lewy bodies, Proceedings of the National Academy of Sciences, vol.95, issue.11, pp.6469-6473, 1998. ,
, , 1997.
, Alpha-synuclein in Lewy bodies, Nature, vol.388, issue.6645, pp.839-840
1041 Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's 1042 disease and dementia with Lewy bodies, Neuroscience letters, vol.251, issue.3, pp.205-208, 1998. ,
2012. alpha-Synuclein in Parkinson's disease. Cold Spring Harb Perspect Med 1044, vol.2, p.9399 ,
, , p.1046
, , 1047.
Solid-state NMR 1048 structure of a pathogenic fibril of full-length human alpha-synuclein, Nat Struct Mol 1049 Biol, vol.23, issue.5, pp.409-415, 2016. ,
Molecular cloning of cDNA encoding an unrecognized 1052 component of amyloid in Alzheimer disease, Proc Natl Acad Sci U S A, vol.90, issue.23, pp.1053-11282, 1993. ,
Further 1055 exploration of the conformational space of alpha-synuclein fibrils: solid-state NMR 1056 assignment of a high-pH polymorph, Biomol NMR Assign, vol.10, issue.1, pp.5-12, 2016. ,
, , p.1058
The fold of alpha-synuclein fibrils, Proc Natl Acad Sci 1059 U S A 105, pp.8637-8642, 2008. ,
Atomic-resolution structure of a disease-relevant Abeta(1-42) 1062 amyloid fibril, Proc Natl Acad Sci U S A, vol.113, issue.34, pp.4976-4984, 2016. ,
Caspase-1 causes truncation and aggregation of the Parkinson's disease-1067 associated protein ?-synuclein, Proceedings of the National Academy of Sciences, vol.1068, issue.34, pp.9587-9592, 1066. ,
, , vol.3, p.1071
1072 MolProbity: More and better reference data for improved all-atom structure 1073 validation, Protein Sci, vol.27, issue.1, pp.293-315, 2018. ,
, , p.1075
, , p.1076
The new mutation, E46K, of alpha-synuclein 1077 causes Parkinson and Lewy body dementia, Annals of neurology, vol.55, issue.2, pp.164-173, 2004. ,
, , p.1080, 1079.
, Alzheimer's and Pick's diseases. Elife 8(e43584)
1082 MotionCor2: anisotropic correction of beam-induced motion for improved cryo-1083 electron microscopy, Nat Methods, vol.14, issue.4, pp.331-332, 2017. ,
New tools for automated high-resolution cryo-EM structure determination 1086 in RELION-3, vol.7, 2018. ,