title: Lysosomal Enzyme Glucocerebrosidase Protects against Aβ1-42 Oligomer-Induced Neurotoxicity.
abstract: Glucocerebrosidase (GCase) functions as a lysosomal enzyme and its mutations are known to be related to many neurodegenerative diseases, including Gaucher's disease (GD), Parkinson's disease (PD), and Dementia with Lewy Bodies (DLB). However, there is little information about the role of GCase in the pathogenesis of Alzheimer's disease (AD). Here we demonstrate that GCase protein levels and enzyme activity are significantly decreased in sporadic AD. Moreover, Aβ1-42 oligomer treatment results in neuronal cell death that is concomitant with decreased GCase protein levels and enzyme activity, as well as impairment in lysosomal biogenesis and acidification. Importantly, overexpression of GCase promotes the lysosomal degradation of Aβ1-42 oligomers, restores the lysosomal impairment, and protects against the toxicity in neurons treated with Aβ1-42 oligomers. Our findings indicate that a deficiency of GCase could be involved in progression of AD pathology and suggest that augmentation of GCase activity may be a potential therapeutic option for the treatment of AD.
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana, United States of America.
authors.forename: Seulah
authors.initials: S
authors.lastname: Choi
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana, United States of America.
authors.forename: Donghoon
authors.initials: D
authors.lastname: Kim
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Tae-In
authors.initials: TI
authors.lastname: Kam
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana, United States of America.
authors.forename: Seungpil
authors.initials: S
authors.lastname: Yun
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Sangjune
authors.initials: S
authors.lastname: Kim
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Park
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Heehong
authors.initials: H
authors.lastname: Hwang
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana, United States of America.
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana, United States of America.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana, United States of America.
authors.forename: Han Seok
authors.initials: HS
authors.lastname: Ko
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D005962:Glucosylceramidase / Q000378:metabolism*; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000066829:Neuroprotection; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D059748:Proteolysis
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D005962:Glucosylceramidase