Autophagy modulates alpha-Synuclein cellular pathology and exosome associated release

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Synucleinopathies including Parkinson disease (PD) and Dementia with Lewy bodies (DLB) are characterized by cytoplasmic and neuritic inclusions (Lewy bodies, LBs, and Lewy neurites, LNs) composed of misfolded and aggregated forms of alpha-synuclein aSyn. Complementary to the ubiquitin-proteasome degradation system (UPS) aSyn is degraded by the autophagy-lysosomal pathway (ALP). Recently, we analyzed the role of the ALP on aggregated forms of aSyn in vitro and in vivo models of aSyn aggregation where we identified a direct role of ALP not only on aSyn aggregation and toxicity, but surprisingly also to extracellular release of aSyn (Autophagy 2012, 2014). The multivesicular body compartment (MVB) might be the interconnecting cellular mechanism that links intracellular degradation to extracellular release and pathology. Since exosomes derive form MVB and have recently associated with aSyn release mechanisms, the present grant aims to understand if 1) ALP modulation affects intracellular aSyn pathology and induces exosome-dependent aSyn release mechanisms, 2) toxic aSyn species released by the exosome secretion pathway (ESP) derived from the MVB intersect with the autophagy modulated degradation pathways (ALP), and 3) if ALP and ESP modulation affects the extracellular response of neuronal (propagation) and glial cells (proinflammation) to released aSyn and thereby contributes to its pathomechanism. Intracellular pathology, extracellular release and response to neural cells will be studied in human aSyn cell culture models. In parallel, a second set of experiments will test these effects in primary neuronal cultures from human aSyn promoter driven aSyn transgenic mice (on aSyn k.o. background), and in neural cocultures. In summary, the proposed project will integrate the important role of ALP on intracellular aSyn with the recently identified role of extracellular aSyn in neuronal-glial communication, transfer, toxicity, and disease progression.