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J Neurochem. 2017 Feb;140(4):662-678. doi: 10.1111/jnc.13743. Epub 2016 Aug 19.

Proteolysis of α-synuclein fibrils in the lysosomal pathway limits induction of inclusion pathology.

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Department of Neuroscience, College of Medicine University of Florida, Gainesville, Florida, USA.
Center for Translational Research in Neurodegenerative Disease, College of Medicine University of Florida, Gainesville, Florida, USA.
McKnight Brain Institute, College of Medicine University of Florida, Gainesville, Florida, USA.


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 intraneuronal 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 over-expressing 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. Cover Image for this issue: doi: 10.1111/jnc.13787.


Parkinson's disease; degradation; endocytosis; inclusions; lysosome; α-synuclein

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