Morphogenesis of Lewy Bodies: Dissimilar Incorporation of α-Synuclein, Ubiquitin, and p62

The formation of Lewy bodies (LBs) and their relationship to other types of nigral inclusions associated with Parkinson disease (PD), such as pale bodies (PBs), remain poorly understood. Known constituents of LBs include alpha-synuclein (alphaS) and ubiquitin (Ub), providing windows to their morphogenesis. Additionally, p62/sequestosome 1 has been identified as a common component of neuropathological and hepatocytic inclusions. To study the formation of PD-associated nigral inclusions, we analyzed the substantia nigra of cases with abundant LBs and PBs in hematoxylin and eosin (H&E) stain, using immunohistochemistry for alphaS, Ub, and p62. We found morphologically diverse alphaS-immunoreactive deposits within neuronal perikarya and neurites. Perikaryal types extended from punctate cytoplasmic staining to variform compact (i.e. PB-type and LB-type) inclusions. Using H&E, only a small subset of the compact deposits could be unambiguously identified. Labeling for p62 was highly similar to alphaS in compact perikaryal inclusions, whereas no punctate staining or intraneuritic inclusions were detected. Ubiquitin antibodies labeled compact deposits both within perikarya and neurites. The data suggest that pathological alphaS is first evident as punctate perikaryal material that, via coalescence and incorporation of p62 and Ub, yields PB-type structures from which LB-type inclusions form in a compaction-like manner. The results also point at dissimilarities in the formation of perikaryal vs intraneuritic inclusions.