Defining a Lewy Body: Running Up the Hill of Shifting Definitions and Evolving Concepts

Abstract

Lewy bodies (LBs) are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies, characterized by the accumulation of α-synuclein (αSyn) protein in the brain. While LBs were first described a century ago, their formation and morphogenesis mechanisms remain incompletely understood. Here, we present a historical overview of LB definitions and highlight the importance of semantic clarity and precise definitions when describing brain inclusions. Recent breakthroughs in imaging revealed shared features within LB subsets and the enrichment of membrane-bound organelles in these structures, challenging the conventional LB formation model. We discuss the involvement of emerging concepts of liquid-liquid phase separation, where biomolecules demix from a solution to form dense condensates, as a potential LB formation mechanism. Finally, we emphasize the need for the operational definitions of LBs based on morphological characteristics and detection protocols, particularly in studies investigating LB formation mechanisms. A better understanding of LB organization and ultrastructure can contribute to the development of targeted therapeutic strategies for synucleinopathies.

Keywords: Lewy body; Parkinson’s disease; aggregation; liquid-liquid phase separation; α-synuclein.

Fig. 1

Conceptualization of ‘LBs’ in the midbrain versus the cortex based on most commonly used markers. In the midbrain (A), a LB is often referred to as a subset of neuronal perikaryal inclusions that are immunopositive for αSyn and ubiquitin, and further fulfill several other criteria (e.g., morphological) criteria, and positive H&E staining. Together, this highlights the conceptual difference between a subset of well-defined inclusions among a larger group of different-appearing heterogeneous inclusion types (e.g., pale bodies). In contrast, in the cortex (B), any perikaryal inclusion that is immunopositive for ubiquitin or αSyn is termed a ‘LB’, consequently encompassing a large spectrum of ill-defined structures, ranging from, e.g., compact and globular to expanding uniform cytoplasmic fillings (discussed further in text). Micrographs showing Ser129-immunoreactive (antibody: 11A5) inclusions in SNpc and cortex are modified from Moors et al., 2021 [54], where the images were published under a CC-BY 4.0 license.

Fig. 2

αSyn as a potential surfactant of complex inclusions in synaptic physiology and Lewy body pathology. A) Synaptic condensates readily recruit α-synuclein. Top: αSyn interacts with synapsin 1 droplets in HEK cells. Bottom: αSyn readily recovers fluorescence after photobleaching indicating its high mobility in condensates. B) 3D reconstruction of a nigral Lewy body indicating the accumulation of phosphorylated αSyn at the interface of pathological inclusions. C) Scheme of the interaction between a lipid vesicle and α-synuclein. The size of folded domains of α-synuclein (PDB: 1XQ8) and lipid vesicle are to scale. αSyn residues mutated in some patients with familial Parkinson’s Disease are highlighted in magenta. D) Computational examples of a protein-like polymer indicating the different chemical potential and interaction landscape in a condensate (i.e., dense phase; red circle) in comparison to a dilute phase (green circle). E) A model suggesting that soluble proteins such as αSyn reversibly form condensates in heathy cells. In pathology, however, the proteins within a condensate might undergo internal rearrangements with an ensemble of molecules accumulating with a stereotypic orientation at the interface resulting in the formation of an outer layer and reducing the overall reversibility of condensates. The images in A, B and D are modified from Hoffmann et al., 2021 [80]; Moors et al., 2021 [54]; Farag et al., 2022 [114], where the images were published under a CC-BY 4.0 license.