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: You-hai Xu, Kui Xu, Ying Sun, Benjamin Liou, Brian Quinn, Rong-hua Li, Ling Xue, Wujuan Zhang, Kenneth D R Setchell, David Witte, Gregory A Grabowski
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 23 Issue 15 Pg. 3943-57 (Aug 01 2014) ISSN: 1460-2083 [Electronic] England
• PMID: 24599400 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Amyloid beta-Protein Precursor
• Enzyme Inhibitors
• Lamp1 protein, mouse
• Lysosome-Associated Membrane Glycoproteins
• Map1lc3b protein, mouse
• Membrane Transport Proteins
• Microtubule-Associated Proteins
• Mitochondrial Proteins
• alpha-Synuclein
• mitochondrial outer membrane protein 35-kDa, mouse
• Inositol
• Prostaglandin-Endoperoxide Synthases
• beta-Glucosidase
• conduritol epoxide

Topics

• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Cells, Cultured
• Cerebral Cortex (metabolism, pathology)
• Corpus Striatum (metabolism, pathology)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Gaucher Disease (genetics, metabolism, pathology)
• Gene Expression Regulation
• Hippocampus (metabolism, pathology)
• Humans
• Inositol (analogs & derivatives, pharmacology)
• Lysosome-Associated Membrane Glycoproteins (genetics, metabolism)
• Membrane Transport Proteins (genetics, metabolism)
• Mice
• Microtubule-Associated Proteins (genetics, metabolism)
• Mitochondria (metabolism, pathology)
• Mitochondrial Proteins (genetics, metabolism)
• Neurons (metabolism, pathology)
• Prostaglandin-Endoperoxide Synthases (genetics, metabolism)
• Protein Aggregation, Pathological
• Substantia Nigra (metabolism, pathology)
• alpha-Synuclein (genetics, metabolism)
• beta-Glucosidase (antagonists & inhibitors, genetics, metabolism)