title: Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice.
abstract: Gaucher disease, a prevalent lysosomal storage disease (LSD), is caused by insufficient activity of acid β-glucosidase (GCase) and the resultant glucosylceramide (GC)/glucosylsphingosine (GS) accumulation in visceral organs (Type 1) and the central nervous system (Types 2 and 3). Recent clinical and genetic studies implicate a pathogenic link between Gaucher and neurodegenerative diseases. The aggregation and inclusion bodies of α-synuclein with ubiquitin are present in the brains of Gaucher disease patients and mouse models. Indirect evidence of β-amyloid pathology promoting α-synuclein fibrillation supports these pathogenic proteins as a common feature in neurodegenerative diseases. Here, multiple proteins are implicated in the pathogenesis of chronic neuronopathic Gaucher disease (nGD). Immunohistochemical and biochemical analyses showed significant amounts of β-amyloid and amyloid precursor protein (APP) aggregates in the cortex, hippocampus, stratum and substantia nigra of the nGD mice. APP aggregates were in neuronal cells and colocalized with α-synuclein signals. A majority of APP co-localized with the mitochondrial markers TOM40 and Cox IV; a small portion co-localized with the autophagy proteins, P62/LC3, and the lysosomal marker, LAMP1. In cultured wild-type brain cortical neural cells, the GCase-irreversible inhibitor, conduritol B epoxide (CBE), reproduced the APP/α-synuclein aggregation and the accumulation of GC/GS. Ultrastructural studies showed numerous larger-sized and electron-dense mitochondria in nGD cerebral cortical neural cells. Significant reductions of mitochondrial adenosine triphosphate production and oxygen consumption (28-40%) were detected in nGD brains and in CBE-treated neural cells. These studies implicate defective GCase function and GC/GS accumulation as risk factors for mitochondrial dysfunction and the multi-proteinopathies (α-synuclein-, APP- and Aβ-aggregates) in nGD.
authors.affiliation: The Division of Human Genetics and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: You-hai
authors.initials: YH
authors.lastname: Xu
authors.affiliation: The Division of Human Genetics and.
authors.forename: Kui
authors.initials: K
authors.lastname: Xu
authors.affiliation: The Division of Human Genetics and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: The Division of Human Genetics and.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Liou
authors.affiliation: The Division of Human Genetics and.
authors.forename: Brian
authors.initials: B
authors.lastname: Quinn
authors.affiliation: The Division of Human Genetics and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: Rong-hua
authors.initials: RH
authors.lastname: Li
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical College, Wenzhou, Zhejiang, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xue
authors.affiliation: The Division of Pathology and Laboratory, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA.
authors.forename: Wujuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The Division of Pathology and Laboratory, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: Kenneth D R
authors.initials: KD
authors.lastname: Setchell
authors.affiliation: The Division of Pathology and Laboratory, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: David
authors.initials: D
authors.lastname: Witte
authors.affiliation: The Division of Human Genetics and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA Synageva BioPharma, Lexington, MA 02421, USA gregory.grabowski@synageva.com.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005776:Gaucher Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives / Q000494:pharmacology; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D007294:Inositol; D051907:Lysosomal Membrane Proteins; D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D051844:alpha-Synuclein; D001617:beta-Glucosidase; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C480860:Map1lc3b protein, mouse; C455940:mitochondrial outer membrane protein 35-kDa, mouse; C011423:conduritol epoxide