Former Graduate Student, Dr. Amanda Sacino & colleagues publish in July 2016 Journal of Neurochemistry

Proteolysis of α-Synuclein Fibrils in the Lysosomal Pathway Limits Induction of Inclusion Pathology. – PubMed – NCBI.  Sacino AN, Brooks MM, Chakrabarty P, Saha K, Khoshbouei H, Golde TE, Giasson BI.  J Neurochem 2016.

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

This article is protected by copyright. All rights reserved.

KEYWORDS:  Parkinson’s disease; degradation; endocytosis; inclusions; lysosome; α-synuclein