Summary
Parkinson’s disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy neurites, which are neuronal inclusions that are immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of Lewy pathology is key to understanding pathogenesis and progression of the disease. Using correlative light and electron microscopy on postmortem brain tissue of Parkinson’s patients, we discovered a crowded membranous medley of vesicular structures, dysmorphic mitochondria and disrupted cytoskeletal elements in Lewy bodies and Lewy neurites, rather than the widely expected proteinacious filaments. The collapse and crowding of central organellar components was confirmed by stimulated emission-depletion microscopy, and chemical and optical imaging. A high lipid content was confirmed by lipidomics. The findings indicate ill-defined subcellular protein-lipid compartmentalization and point toward impaired organellar trafficking as a key driver of pathogenesis in Parkinson’s disease.
