Several lines of evidence from neuropathological studies, human genetics, in vitro aggregation studies and cellular and animal models support the hypothesis that aSyn plays a central role in the formation of Lewy pathologies. These are cytoplasmic proteinaceous and lipid-rich inclusions that represent key pathological hallmarks of Parkinson’s disease (PD) and other neurodegenerative diseases, collectively referred to as synucleinopathies. For decades, light microscopy and electron microscopy studies of these inclusions have consistently shown that they are rich in filamentous structures that exhibit distinct distribution and organizational patterns depending on where they occur in the brain (e.g., classical brain-stem Lewy bodies (LBs) and cortical LBs) and the type of synucleinopathies. Although the identity of the protein that form these filaments was a subject of debate for decades, the discovery of PD-linked aSyn mutations, the demonstration that LBs are enriched in insoluble forms of aSyn, and the ability of aSyn to form fibrils of similar dimensions have led to convergence on the hypothesis that aSyn fibrils are key components of LBs. In a recent study, Shahmoradian et al used a combination of advanced electron microscopy and immunofluorescence based imaging techniques to investigate the structure, composition, and architecture of LBs from postmortem brain tissues of individuals with PD or other synucleinopathies (Shahmoradian et al., 2019). The paper’s main conclusions suggest that “lipid membrane fragments and distorted organelles together with a non-fibrillar form of αSyn are the main structural building blocks for the formation of Lewy pathology”. Their proposal that LBs are devoid of aSyn fibrils or that LB formation occurs independently of aSyn fibril formation casts doubts on a substantial body of work that forms the foundation of many of the current basic and translational research programs in academia and industry. In this article, I present a critical analysis of their data and claims in the context of the existing literature In addition, I examine the extent to which their findings and proposed models of the mechanisms of LB formation are consistent with existing data and are supported by other experimental evidence. The results from this analysis caution against overinterpretation of observations from a single report, especially given the limitations of the techniques and experimental approaches used by Shahmoradian et al and for more collaborative and systematic efforts to revisit and characterize LBs and other aSyn pathologies in the brain pathologies at the biochemical, morphological and structural level.
