title: Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.
abstract: Parkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of α-synuclein (α-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified α-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that α-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of α-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mazzulli
authors.forename: You-Hai
authors.initials: YH
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Adam L
authors.initials: AL
authors.lastname: Knight
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McLean
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.forename: Ellen
authors.initials: E
authors.lastname: Sidransky
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D005776:Gaucher Disease / Q000378:metabolism* / Q000473:pathology; D005962:Glucosylceramidase / Q000378:metabolism*; D005963:Glucosylceramides / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D005963:Glucosylceramides; D051844:alpha-Synuclein; D005962:Glucosylceramidase