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Reverse engineering Lewy bodies: how far have we come and how far can we go?

A Publisher Correction to this article was published on 02 March 2021

This article has been updated

Abstract

Lewy bodies (LBs) are α-synuclein (α-syn)-rich intracellular inclusions that are an important pathological hallmark of Parkinson disease and several other neurodegenerative diseases. Increasing evidence suggests that the aggregation of α-syn has a central role in LB formation and is one of the key processes that drive neurodegeneration and pathology progression in Parkinson disease. However, little is known about the mechanisms underlying the formation of LBs, their biochemical composition and ultrastructural properties, how they evolve and spread with disease progression, and their role in neurodegeneration. In this Review, we discuss current knowledge of α-syn pathology, including the biochemical, structural and morphological features of LBs observed in different brain regions. We also review the most used cellular and animal models of α-syn aggregation and pathology spreading in relation to the extent to which they reproduce key features of authentic LBs. Finally, we provide important insights into molecular and cellular determinants of LB formation and spreading, and highlight the critical need for more detailed and systematic characterization of α-syn pathology, at both the biochemical and structural levels. This would advance our understanding of Parkinson disease and other neurodegenerative diseases and allow the development of more-reliable disease models and novel effective therapeutic strategies.

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Fig. 1: Histological properties and proposed staging of cortical and brainstem Lewy bodies and Lewy neurites from patients with Parkinson disease.
Fig. 2: Diversity of immunostaining patterns of cortical and brainstem Lewy bodies from patients with PD.
Fig. 3: A proposed model for the de novo formation of Lewy bodies.
Fig. 4: A model for the spreading of fibrillar α-synuclein pathology.
Fig. 5: Tools and platforms for dissecting the diversity of Lewy bodies and evaluating the α-synuclein aggregation states in cellular and animal models.

Change history

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Acknowledgements

The authors are grateful to A.-L. Mahul-Mellier, R. Hegde, S. Donzelli, S. Novello, I. Rostami and N. Riguet for their critical inputs regarding supplementary tables 2 and 3, and thank G. Limorenko, R. Hegde and S. Novello for help in revising galley proofs.

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The authors contributed equally to all aspects of the article.

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Correspondence to Mohamed Bilal Fares or Hilal A. Lashuel.

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H.A.L. has received funding from industry to support research on neurodegenerative diseases, including from Merck Serono, UCB and Abbvie. These companies had no specific role in the in the conceptualization and preparation of and decision to publish this work. H.A.L is also the co-founder and Chief Scientific Officer of ND BioSciences SA, a company that develops diagnostics and treatments for neurodegenerative diseases based on platforms that reproduce the complexity and diversity of proteins implicated in neurodegenerative diseases and their pathologies. M.B.F. is a co-founder of ND BioSciences SA and Director of Research and Development in the company. S.J. declares no competing interests.

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Nature Reviews Neuroscience thanks S. Gentleman, M. Hasegawa and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Inclusions

A term commonly used to describe the localized accumulation of proteins in cells or tissues as determined by their immunoreactivity to specific antibodies or detection of fluorescent puncta when the protein of interest is fused to fluorescent proteins. Not all inclusions represent the accumulation of aggregated proteins, unless verified by other biophysical or biochemical techniques.

Lewy bodies

(LBs). One of the key pathological hallmarks of Parkinson disease and other synucleinopathies. They comprise intracellular globular cytoplasmic inclusions that contain complex mixtures of proteins, lipids and membranous organelles, and are enriched in aggregated forms of α-synuclein, predominantly insoluble fibrillar species.

Lewy neurites

(LNs). A pathological hallmark of Parkinson disease. These are dystrophic processes containing protein accumulations that share many of the biochemical and immunohistological properties of Lewy bodies, including the presence of phosphorylated filamentous α-synuclein aggregates, although their ultrastructural features and biochemical composition remain less well characterized.

Propagation

A term that refers to the process underlying the spreading of pathological aggregates in the brain through the transfer of seeding-competent protein aggregates from one cell to another.

Oligomers

Soluble peptide or protein assemblies (dimers or multimers) that exhibit different sizes, secondary structures and shapes (for example, spherical, pore-like and curvilinear structures).

Fibrils

Insoluble filamentous structures (8–12 nm in diameter) that form as a result of the misfolding and self-assembly of a peptide or a protein (for example, α-synuclein) via formation of repeating β-sheet structures, also known as cross-β structure, which is responsible for their unique binding to specific dyes (for example, thioflavin T, thioflavin S, Amytracker and Congo red), and allows them to be distinguished from other β-sheet-rich proteins.

Amorphous aggregates

Aberrant protein aggregates that do not exhibit a specific ordered organization or morphology, that is, they are non-fibrillar.

Pale bodies

Usually referred to as precursors to Lewy bodies, pale bodies are proteinaceous accumulations enriched with aggregated α-synuclein but do not exhibit many of the morphological, organizational and biochemical properties of mature Lewy bodies.

Seeds

Relatively stable aggregates that can be prepared in vitro (such as fragmented fibrils) or isolated from pathological inclusions (such as Lewy bodies or glial cytoplasmic inclusions), total brain homogenates or the cerebrospinal fluid of patients with Parkinson disease or other synucleinopathies. When added to solutions or cells that have monomeric α-syn subunits, seeds accelerate their conversion to fibrils (in vitro) or to fibrils and Lewy body-like structures in neurons.

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Fares, M.B., Jagannath, S. & Lashuel, H.A. Reverse engineering Lewy bodies: how far have we come and how far can we go?. Nat Rev Neurosci 22, 111–131 (2021). https://doi.org/10.1038/s41583-020-00416-6

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