Mitochondria and quality control defects in a mouse model of Gaucher disease--links to Parkinson's disease.
Cell Metab
; 17(6): 941-953, 2013 Jun 04.
Article
em En
| MEDLINE
| ID: mdl-23707074
ABSTRACT
Mutations in the glucocerebrosidase (gba) gene cause Gaucher disease (GD), the most common lysosomal storage disorder, and increase susceptibility to Parkinson's disease (PD). While the clinical and pathological features of idiopathic PD and PD related to gba (PD-GBA) mutations are very similar, cellular mechanisms underlying neurodegeneration in each are unclear. Using a mouse model of neuronopathic GD, we show that autophagic machinery and proteasomal machinery are defective in neurons and astrocytes lacking gba. Markers of neurodegeneration--p62/SQSTM1, ubiquitinated proteins, and insoluble α-synuclein--accumulate. Mitochondria were dysfunctional and fragmented, with impaired respiration, reduced respiratory chain complex activities, and a decreased potential maintained by reversal of the ATP synthase. Thus a primary lysosomal defect causes accumulation of dysfunctional mitochondria as a result of impaired autophagy and dysfunctional proteasomal pathways. These data provide conclusive evidence for mitochondrial dysfunction in GD and provide insight into the pathogenesis of PD and PD-GBA.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
/
Doenças Mitocondriais
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Doença de Gaucher
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Glucosilceramidase
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Mitocôndrias
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article