Current insights and assumptions on α-synuclein in Lewy body disease

Abstract

Lewy body disorders are heterogeneous neurological conditions defined by intracellular inclusions composed of misshapen α-synuclein protein aggregates. Although α-synuclein aggregates are only one component of inclusions and not strictly coupled to neurodegeneration, evidence suggests they seed the propagation of Lewy pathology within and across cells. Genetic mutations, genomic multiplications, and sequence polymorphisms of the gene encoding α-synuclein are also causally linked to Lewy body disease. In nonfamilial cases of Lewy body disease, the disease trigger remains unidentified but may range from industrial/agricultural toxicants and natural sources of poisons to microbial pathogens. Perhaps due to these peripheral exposures, Lewy inclusions appear at early disease stages in brain regions connected with cranial nerves I and X, which interface with inhaled and ingested environmental elements in the nasal or gastrointestinal cavities. Irrespective of its identity, a stealthy disease trigger most likely shifts soluble α-synuclein (directly or indirectly) into insoluble, cross-β-sheet aggregates. Indeed, β-sheet-rich self-replicating α-synuclein multimers reside in patient plasma, cerebrospinal fluid, and other tissues, and can be subjected to α-synuclein seed amplification assays. Thus, clinicians should be able to capitalize on α-synuclein seed amplification assays to stratify patients into potential responders versus non-responders in future clinical trials of α-synuclein targeted therapies. Here, we briefly review the current understanding of α-synuclein in Lewy body disease and speculate on pathophysiological processes underlying the potential transmission of α-synucleinopathy across the neuraxis.

Keywords: Dementia; Lewy body; Neurodegeneration; Parkinson’s disease; Prion; Synuclein.

Fig. 1

Bulk tissue expression of SNCA according the GTEx online data portal hosted by the Broad Institute of MIT and Harvard. The Y axis is shown on a linear scale and the X axis is sorted alphabetically according to tissue type or brain region. Note the high median expression of SNCA within human cerebellar tissues, discussed below alongside Fig. 2. These violin plots were retrieved from the GTEx portal on July 27, 2024 at this link: https://www.gtexportal.org/home/gene/SNCA

Fig. 2

Allen Brain Atlas in situ mRNA hybridization for Snca, the mouse gene encoding α-synuclein [134]. A–D Sagittal brain sections from a 56-day-old C57BL/6 J male mouse are shown from medial to lateral, with high expression of α-synuclein mRNA in the dorsomotor nucleus of the vagus (DMV), the substantia nigra pars compacta (SNpc), the pyramidal and granule cells of the hippocampus (HP), and the mitral cell layer of the olfactory bulb (OBml). Moderate expression is seen in the ventral tegmental area (VTA), anterior olfactory nucleus (AON), the locus coeruleus (LC), the subiculum (Sub), the cortical amygdala (CoA), the piriform cortex (Piri CTX). There is low expression of Snca in the olfactory tubercle (OT), cerebellum (CB), and white matter (unlabeled). Antisense data were retrieved from the Allen Institute at this link: https://mouse.brain-map.org/experiment/siv?id=79904550&imageId=79764405&initImage=expression&contrast=0.5,0.5,0,255,4

Fig. 3

DropViz database ranking of top ten mouse brain cell clusters with the highest expression of Snca [207]. Note the high expression of Snca in cerebellar neurons and in hippocampal neurons, consistent with mouse data in Fig. 2d. Retrieved from http://dropviz.org

Fig. 4

Microglia/macrophages may engulf neurons that house exogenous, preformed fibrils. Phosphate-buffered saline (PBS) or ATTO₆₄₇ preformed fibrils (PFFs) were sonicated and infused in the bulbar anterior olfactory nucleus in genetically outbred CD-1 mice of both sexes, as described [21]. Mice were sacrificed 3 h or 3–6 days later for immunostaining with antibodies against the pan-microglia/macrophage marker Iba1 (Wako 01919741) and the neuronal nuclear marker NeuN (Millipore ABN90). The Hoechst reagent was applied to label all nuclei. A Infusion site in the dorsal anterior olfactory nucleus and the caudal olfactory bulb. B The labeled markers are shown in isolation (for clarity) or in merged form at three days post-infusion. Note the Iba1⁺ cell partially enfolding a NeuN⁺ cell. Most PFFs at the site of infusion were in NeuN⁺ neurons rather than NeuN⁻ profiles. Thus, we speculate that neurons may be unable to fully degrade aggregates—or else the PFF model would not work. C Shown is a confocal Z-slice at the intersection of an Iba1⁺ object engulfing a NeuN⁺ object that houses fluorescent PFFs. D–E Three-dimensional Imaris rendering of the cell from panel C. A second representative example is included on the left of panel D