Abstract
Cell-to-cell propagation of aggregated alpha synuclein (aSyn) has been suggested to play an important role in the progression of alpha synucleinopathies. A critical step for the propagation process is the accumulation of extracellular aSyn within recipient cells. Here, we investigated the trafficking of distinct exogenous aSyn forms and addressed the mechanisms influencing their accumulation in recipient cells. The aggregated aSyn species (oligomers and fibrils) exhibited more pronounced accumulation within recipient cells than aSyn monomers. In particular, internalized extracellular aSyn in the aggregated forms was able to seed the aggregation of endogenous aSyn. Following uptake, aSyn was detected along endosome-to-lysosome and autophagosome-to-lysosome routes. Intriguingly, aggregated aSyn resulted in lysosomal activity impairment, accompanied by the accumulation of dilated lysosomes. Moreover, analysis of autophagy-related protein markers suggested decreased autophagosome clearance. In contrast, the endocytic pathway, proteasome activity, and mitochondrial homeostasis were not substantially affected in recipient cells. Our data suggests that extracellularly added aggregated aSyn primarily impairs lysosomal activity, consequently leading to aSyn accumulation within recipient cells. Importantly, the autophagy inducer trehalose prevented lysosomal alterations and attenuated aSyn accumulation within aSyn-exposed cells. Our study underscores the importance of lysosomes for the propagation of aSyn pathology, thereby proposing these organelles as interventional targets.
Highlights
Alpha synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy, are characterized by intracellular deposition of alpha synuclein[1,2,3]
To address whether the uptake efficiency of alpha synuclein (aSyn) differs between its aggregation states, we first analyzed the accumulation of extracellularly added aSyn in human neuroglioma (H4) cells exposed to unlabeled aSyn monomers as well as preformed oligomers and fibrils
Due to the possibility that aSyn species may change their assembly after adding to cells, we use the term “extracellular aSyn”, indicating aSyn in the extracellular spaces and extracellularly added aSyn species in their original aggregation states, and the term “exogenous aSyn”, referring to aSyn that accumulates or is internalized in recipient cells
Summary
Alpha synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy, are characterized by intracellular deposition of alpha synuclein (aSyn)[1,2,3]. In addition to pathological aSyn aggregation, mitochondrial dysfunction and impaired protein degradation pathways, including the autophagy-lysosomal pathway (ALP) and the ubiquitin-proteasome system, have been linked to the neurodegeneration in alpha synucleinopathies[5,6,7]. Of PD patients correlated with the clinical stages of patients[10], suggesting a progressive spreading of aSyn pathology between brain regions; (3) embryonic mesencephalic neurons grafted into the neostriatum of PD patients developed Lewy bodies[11,12]. For achieving cell-to-cell propagation, it is crucial that internalized extracellular aSyn bypasses the protein degradation pathways, such as ALP and ubiquitin-proteasome system, accumulates within recipient cells, and interacts with endogenous aSyn and other cellular targets. We investigated the trafficking behavior of extracellularly added aSyn in different aggregation states and characterized the target pathways in recipient cells. We further found that activation of lysosomal function by trehalose significantly prevents aSyn pathology in recipient cells
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