Proteolysis Of Alpha-Synuclein Fibrils In The Lysosomal Pathway Limits Induction Of Inclusion Pathology

Progression of alpha-synuclein inclusion pathology may occur through cycles of release and uptake of alpha-synuclein aggregates, which induce additional intracellular alpha-synuclein inclusion pathology. This process may explain (i) the presence of alpha-synuclein inclusion pathology in grafted cells in human brains, and (ii) the slowly progressive nature of most human alpha-synucleinopathies. It also provides a rationale for therapeutic targeting of extracellular aggregates to limit pathology spread. We investigated the cellular mechanisms underlying intraneuronal alpha-synuclein aggregation following exposure to exogenous preformed alpha-synuclein amyloid fibrils. Exogenous alpha-synuclein fibrils efficiently attached to cell membranes and were subsequently internalized and degraded within the endosomal/lysosomal system. However, internalized alpha-synuclein amyloid fibrils can apparently overwhelm the endosomal/lysosomal machinery leading to the induction of intraneuronal alpha-synuclein inclusions comprised of endogenous alpha-synuclein. Furthermore, the efficiency of inclusion formation was relatively low in these studies compared to studies using primary neuronal-glial cultures over-expressing alpha-synuclein. Our study indicates that under physiologic conditions, endosomal/lysosomal function acts as an endogenous barrier to the induction of alpha-synuclein inclusion pathology, but when compromised, it may lower the threshold for pathology induction/transmission.