Format

Send to

Choose Destination
Hum Mol Genet. 2014 Aug 1;23(15):3943-57. doi: 10.1093/hmg/ddu105. Epub 2014 Mar 5.

Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice.

Author information

1
The Division of Human Genetics and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
2
The Division of Human Genetics and.
3
Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical College, Wenzhou, Zhejiang, PR China.
4
The Division of Pathology and Laboratory, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA.
5
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.
6
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.

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.

PMID:
24599400
PMCID:
PMC4082362
DOI:
10.1093/hmg/ddu105
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Publication type

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center