Abstract
Organelle sequestration in Lewy bodies correlates more closely with neurodegeneration than α-synuclein aggregation alone.
Lewy bodies have long been recognized as the hallmark pathology in Parkinson’s disease (PD), and α-synuclein (αSyn) is the main protein component of Lewy bodies. Aggregated forms of αSyn can be neurotoxic, and one theory holds that the formation of Lewy bodies is a cell biological compensatory response to sequester harmful αSyn species. Multiple reports over many years have found other molecules including lipids in Lewy pathology, and a recent manuscript identified organelles and membranous vesicular structures as components of Lewy pathology in humans. Now, Mahul-Mellier et al. have studied the relative contributions of αSyn aggregation and accumulation of cellular organelles to synaptic dysfunction and neurodegeneration.
The authors added αSyn preformed fibrils (PFFs) to cultured neurons and used confocal and electron microscopy to trace the chronicity of (i) αSyn fibrillization; (ii) accumulation of membranous organelles, including mitochondria, autophagosomes, and endolysosomal structures; and (iii) neurodegeneration. Among their findings, they report that αSyn fibrillization occurs early in this process (by 7 days after PFF addition), consistent with data from other groups using similar experimental paradigms; however, the ultrastructural composition observed in human Lewy pathology was best recapitulated 21 days following PFF addition, later than many previous experiments have extended. Furthermore, Mahul-Mellier et al. also reported sequestration of organelles and membranous structures into Lewy pathology, reduction of synaptic markers, and an increase in neuronal cell death between days 14 and 21 after PFF addition.
These findings underscore the complexity of neurodegenerative disease–associated pathology and caution against studying protein aggregation in a vacuum. Additional work is needed to determine precisely which set of molecular and cell biological changes are necessary and sufficient to drive the cell death and network dysfunction that contribute to clinical symptoms in PD, but the data presented here makes a compelling argument to include organelle and lipid membrane recruitment in Lewy pathology as a component of disease severity—especially as an endpoint for trials of disease-modifying therapies in model systems.
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- Copyright © 2020, American Association for the Advancement of Science
