Mitochondria and quality control defects in a mouse model of Gaucher disease--links to Parkinson's disease

Cell Metab. 2013 Jun 4;17(6):941-953. doi: 10.1016/j.cmet.2013.04.014. Epub 2013 May 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Astrocytes / cytology
  • Autophagy / genetics
  • Cells, Cultured
  • Disease Models, Animal
  • Electron Transport
  • Gaucher Disease / genetics
  • Gaucher Disease / metabolism*
  • Glucosylceramidase / genetics*
  • Heat-Shock Proteins / metabolism
  • Humans
  • Lysosomes / genetics
  • Lysosomes / metabolism
  • Mice
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Diseases / genetics*
  • Neurons / cytology
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Sequestosome-1 Protein
  • alpha-Synuclein / metabolism


  • Adaptor Proteins, Signal Transducing
  • Heat-Shock Proteins
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • alpha-Synuclein
  • Glucosylceramidase