title: Proteolysis of α-synuclein fibrils in the lysosomal pathway limits induction of inclusion pathology.
abstract: 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.
authors.affiliation: 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.
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Sacino
authors.affiliation: 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.
authors.forename: Mieu M
authors.initials: MM
authors.lastname: Brooks
authors.affiliation: 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.
authors.forename: Paramita
authors.initials: P
authors.lastname: Chakrabarty
authors.affiliation: Department of Neuroscience, College of Medicine University of Florida, Gainesville, Florida, USA.|McKnight Brain Institute, College of Medicine University of Florida, Gainesville, Florida, USA.
authors.forename: Kaustuv
authors.initials: K
authors.lastname: Saha
authors.affiliation: Department of Neuroscience, College of Medicine University of Florida, Gainesville, Florida, USA.|McKnight Brain Institute, College of Medicine University of Florida, Gainesville, Florida, USA.
authors.forename: Habibeh
authors.initials: H
authors.lastname: Khoshbouei
authors.affiliation: 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.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.affiliation: 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.
authors.forename: Benoit I
authors.initials: BI
authors.lastname: Giasson
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D059748:Proteolysis; D015398:Signal Transduction / Q000502:physiology*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D000682:Amyloid; D051844:alpha-Synuclein
keywords: Parkinson's disease; degradation; endocytosis; inclusions; lysosome; α-synuclein