| First Author | Xu YH | Year | 2014 |
| Journal | Hum Mol Genet | Volume | 23 |
| Issue | 15 | Pages | 3943-57 |
| PubMed ID | 24599400 | Mgi Jnum | J:211000 |
| Mgi Id | MGI:5573012 | Doi | 10.1093/hmg/ddu105 |
| Citation | Xu YH, et al. (2014) Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice. Hum Mol Genet 23(15):3943-57 |
| abstractText | Gaucher disease, a prevalent lysosomal storage disease (LSD), is caused by insufficient activity of acid beta-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 alpha-synuclein with ubiquitin are present in the brains of Gaucher disease patients and mouse models. Indirect evidence of beta-amyloid pathology promoting alpha-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 beta-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 alpha-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/alpha-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 (alpha-synuclein-, APP- and Abeta-aggregates) in nGD. |
