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ULTRASTRUCTURE OF ALPHA-SYNUCLEIN PATHOLOGY PROVIDES NEW INSIGHTS INTO MULTIPLE SYSTEM ATROPHY
Abstract
Aims
Multiple System Atrophy (MSA) is characterized by the accumulation of alpha-synuclein (aSyn) into glial cytoplasmic inclusions (GCIs) and neuronal cytoplasmic inclusions (NCIs). Despite many efforts, it remains unclear which mechanisms lead to their assembly. Thus, in order to increase our understanding of the disease, we investigated the ultrastructure of aSyn immunopositive pathology in the postmortem brain of four MSA donors.
Methods
Brain tissue (substantia nigra and putamen) from clinically diagnosed and pathologically confirmed MSA-P donors with postmortem delays of under 6 hours was processed for correlative light and electron microscopy (CLEM).
Results
We localized 123 GCIs, four microglial cytoplasmic aSyn aggregates and one Lewy body-like NCI. We found that GCIs are composed of a meshwork of fuzzy filaments that colocalized with lysosomes, autophagosomes and peroxisomes. Microglial aSyn aggregates varied in terms of ultrastructures, with some resembling GCIs, while others showed amorphous proteinaceous material without visible filaments. Lysosomes and autophagosomes were also found to colocalize with these aggregates. In contrast to GCIs and the NCIs that have previously been described in MSA literature, we found that the Lewy body-like NCI consisted of a highly dense accumulation of membrane fragments and vesicles, without visible filaments.
Conclusions
We can confirm that GCIs are filamentous and further show that they are composed of various organelles. We also demonstrate the unique ultrastructure of microglial aSyn aggregates and a Lewy body-like NCI for the first time using CLEM in tissue of MSA patients. Together, our findings may ultimately aid in confirming suitable MSA models in the future.