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Conformational strains of pathogenic amyloid proteins in neurodegenerative diseases

Abstract

Amyloid proteins, which are considered ‘villains’ in many neurodegenerative diseases, form enigmatic pathological strains that underlie disease pathogenesis and progression. Recent technical advances in cryogenic electron microscopy and solid-state NMR spectroscopy have enabled the high-resolution structures of full-length amyloid fibrils to be determined, initiating an era in which we have the opportunity to gain atomic-level structural understanding of pathogenic protein aggregation in neurodegenerative diseases. In this Review, we aim to explain the clinicopathological heterogeneity of neurodegenerative diseases by considering the polymorphic structures of amyloid fibrils. We decipher the structural basis for the generation of fibril polymorphs, how the fibril polymorphs differ in different disease contexts and how conformational changes alter the pathology caused by amyloid proteins during disease progression. Finally, we evaluate how this knowledge might aid clinical diagnostic and therapeutic strategies to treat neurodegenerative diseases.

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Fig. 1: Polymorphic strains of pathogenic proteins underlie neurodegenerative disease heterogeneity.
Fig. 2: Structural basis of amyloid fibril polymorphs.
Fig. 3: Changes in α-synuclein polymorphic fibrils in different contexts.
Fig. 4: A model of the pathological profiles of amyloid fibril polymorphs.
Fig. 5: Conformational transition of amyloid fibrils during seeded growth.

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Acknowledgements

The authors thank Y. Ma, Y. Fan and H. Long for assisting with the preparation of figures and tables. They also thank the National Natural Science Foundation of China (grants 82188101, 32170683, 31872716 and 32171236), the Major State Basic Research Development Program (grant 2019YFE0120600), the Science and Technology Commission of Shanghai Municipality (grants 20XD1425000 and 2019SHZDZX02), the Chinese Academy of Science Project for Young Scientists in Basic Research (grant YSBR-009) and the Shanghai Pilot Program for Basic Research–Chinese Academy of Science, Shanghai Branch (grant CYJ-SHFY-2022-005), for funding support.

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Related links

RCSB Protein Data Bank: https://www.rcsb.org/

Glossary

Amyloid fibrils

Insoluble aggregates, formed by repetitive supermolecular assembly of a misfolded protein, in which the protein units are ordered in β-strand-rich structures.

Self-propagation

Process in which preformed amyloid fibrils of a protein nucleate the conversion of the soluble form of the protein into the amyloid form to generate more fibrils.

Cross-β structure

A common structural feature of amyloid fibrils that arises from β-sheet bundles in which the direction of β-strands is nearly perpendicular to the fibril axis.

Cryogenic electron microscopy

(cryo-EM). A transmission electron microscopy technique that is applied to samples that have been rapidly frozen into a glass-like state.

Solid-state NMR spectroscopy

An NMR technology used to investigate the chemical structure and dynamics of solids and semi-solids at an atomic level.

Protein strains

Proteins that form the unique fibril structures that underlie the pathological presentation of a disease.

Conformational strains

Forms of a protein with distinct fibril structures.

Prion diseases

A family of neurodegenerative disorders caused by misfolded prion protein that affect both humans and animals.

Isoforms

Different forms of a protein produced from alternative splicing of the same gene or from similar genes.

Fibril polymorphs

Amyloid fibrils with different structures formed from the same protein.

Post-translational modifications

(PTMs). Biochemical modifications of one or more amino acids within a protein that occur after translation.

Protein misfolding

A common cellular event in which a protein fails to achieve its native structure, resulting in functional abnormality.

Intrinsically disordered proteins

Proteins that lack unique 3D structures but may transit to ordered physiological structures upon interaction with binding partners or to pathological structures under disease conditions.

α-Helix

A type of secondary structure in which the protein chain is coiled as a result of regularly spaced hydrogen bonding between residues and in which the side chains are left reaching outwards.

β-Strand

A type of secondary structure in which the protein chain is extended as a result of the backbone forming hydrogen bonds with the adjacent chains and in which the side chains alternate on both sides.

Free energy

Also called Gibbs free energy. A thermodynamic quantity that expresses the amount of work that can be done by a system. In protein folding, the change of free energy is used to describe the thermodynamic stability of a protein.

Energy landscape

A model that describes protein folding as a funnel-like landscape gradually biased towards the energetically optimal structure.

Cofactors

Substances essential for the construction of the fibril.

Charged pockets

Cavities on the surface or in the interior of a fibril that contain charged residues.

Salt bridges

Electrostatic attractions between oppositely charged amino acid side chains.

β-Hairpin motif

A protein structural motif in which the adjacent antiparallel β-strands are connected either by backbone hydrogen bonding (as usually seen in native structures) or by side chain interactions (as seen in fibril structures).

Seeds

Preformed amyloid fibrils that can serve as a nucleus to template and accelerate the conversion of soluble proteins to fibrils.

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Li, D., Liu, C. Conformational strains of pathogenic amyloid proteins in neurodegenerative diseases. Nat Rev Neurosci (2022). https://doi.org/10.1038/s41583-022-00603-7

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