The 3D structure of lipidic fibrils of α-synuclein

The development of novel drugs for Alzheimer's disease has proven difficult, with a high failure rate in clinical trials. Typically, transgenic mice displaying amyloid-β peptide brain pathology are used to develop therapeutic options and to test their efficacy in preclinical studies. However, the properties of Aβ in such mice have not been systematically compared to Aβ from the patient brains. Here, we determined the structures of nine ex vivo Aβ fibrils from six different mouse models by cryo-EM. We found novel Aβ fibril structures in the APP/PS1, ARTE10, and tg-SwDI models, whereas the human familial type II fibril fold was found in the ARTE10, tg-APPSwe, and APP23 models. The tg-APPArcSwe mice showed an Aβ fibril whose structure resembles the human sporadic type I fibril. These structural elucidations are key to the selection of adequate mouse models for the development of novel plaque-targeting therapeutics and PET imaging tracers.

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“…1 and Fig. S7B), reminiscent of previously described densities on the surface of alpha-synuclein fibrils [32].…”

Section: Additional Densities In Murine Aβ Fibrilssupporting

confidence: 75%

Cryo-EM Structures of Amyloid-β Fibrils from Alzheimer’s Disease Mouse Models

Zielinski

Reyes

Gremer

et al. 2023

Preprint

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“…However, this interaction accounts only partially for the α-SynOs’ neurotoxic effects [ 66 ]. The α-SynO oligomerization process is preferentially located on the membrane surface, and the mitochondrial membranes are more vulnerable to permeabilization [ 23 , 68 , 69 ]. This can be easily associated with the particular vulnerability of mitochondria in PD pathogenesis.…”

Section: Alpha-synuclein Oligomersmentioning

confidence: 99%

“…Numerous investigations have connected the physiological activity of α-Syn in monomeric forms to synaptic functionality [ 21 , 22 ], although there are still no conclusive results about its physiological function, while the pathological events associated with α-Syn are almost exclusively linked to its polymeric forms. Alpha-Syn can bind to lipid membrane, and adopts highly ordered α-helical conformations on lipid binding; the biophysical properties of this interaction have been extensively characterized and associated with α-Syn aggregation mechanisms [ 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

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Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson’s disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.

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“…These data show clusters of lipid molecules in a micelle-like state, either bridging protofilaments or covering the surface of the filaments. MD simulations suggest that these lipid molecules may use their acyl chains to stabilize hydrophobic residues and their polar headgroups to stabilize cationic residues 69 . Our 2D 1 H- 13 C correlation spectra show a complete absence of lipid acyl chain cross peaks with tau, even after extended equilibration (Fig.…”

Section: Discussionmentioning

confidence: 99%

Membrane-induced tau amyloid fibrils

et al. 2023

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The intrinsically disordered protein tau aggregates into β-sheet amyloid fibrils that spread in human brains afflicted with Alzheimer’s disease and other neurodegenerative diseases. Tau interaction with lipid membranes might play a role in the formation and spreading of these pathological aggregates. Here we investigate the conformation and assembly of membrane-induced tau aggregates using solid-state NMR and transmission electron microscopy. A tau construct that encompasses the microtubule-binding repeats and a proline-rich domain is reconstituted into cholesterol-containing phospholipid membranes. 2D 13C-13C correlation spectra indicate that tau converted from a random coil to a β-sheet conformation over weeks. Small unilamellar vesicles (SUVs) cause different equilibrium conformations from large unilamellar vesicles (LUVs) and multilamellar vesicles (MLVs). Importantly, SUV-bound tau developed long fibrils that exhibit the characteristic β-sheet chemical shifts of Tyr310 in heparin-fibrillized tau. In comparison, LUVs and MLVs do not induce fibrils but cause different β-sheet aggregates. Lipid-protein correlation spectra indicate that these tau aggregates reside at the membrane-water interface, without inserting into the middle of the lipid bilayer. Removal of cholesterol from the SUVs abolished the fibrils, indicating that both membrane curvature and cholesterol are required for tau fibril formation. These results have implications for how lipid membranes might nucleate tau aggregates.

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The 3D structure of lipidic fibrils of α-synuclein

Cited by 59 publications

References 65 publications

Cryo-EM Structures of Amyloid-β Fibrils from Alzheimer’s Disease Mouse Models

Cryo-EM Structures of Amyloid-β Fibrils from Alzheimer’s Disease Mouse Models

Alpha Synuclein: Neurodegeneration and Inflammation

Membrane-induced tau amyloid fibrils

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