UCL Queen Square Institute of Neurology


GBA and mitochondria

5 August 2013

Dr Laura Osellame tells us about her recent paper in Cell Metabolism about Mitochondrial dysfunction linked to loss of an enzyme called GBA: Gaucher Disease (GD) is a rare inherited disease, belonging to the family of lysosomal storage disorders. Mutations in the gene glucocerebrosidase (GBA) are responsible for the disease and can increase susceptibility to Parkinson’s disease (PD). Genetic studies undertaken at UCL and other hospitals around the world suggest that mutations in GBA are the most common genetic risk factor currently known for PD.

GBA neurons

The enzyme encoded by GBA – glucocerebrosidase (GCase) is responsible for the conversion of its substrate glucocerebroside (a type of fat) into glucose and ceremide within the lysosome. The lysosome, with its low pH and lytic hydrolyses is responsible for the degradation of proteins and organelles within the autophagic pathway. Autophagy, meaning ‘self eating’ – is the cell’s way of destroying damaged proteins and organelles. Given many of the underlying pathogenic features of neurodegenerative diseases involve accumulation of unwanted/misfolded proteins, the autophagy pathway in relation to PD has garnered much attention of late.

Using a mouse model of GD (in which GBA is knocked out), concentrating on midbrain neurons and astrocytes, we observed global defects in cellular quality control. Downregulation of autophagy, mitophagy (mitochondrial specific induction of autophagy) and the ubiquitin-proteasome system results in accumulation of damaged/fragmented mitochondria, insoluble a-synuclein deposits and ubiquitinated proteins. These quality control pathways are critical for homeostasis of the cell. Without correct turnover and degradation of damaged proteins and organelles, the cell will undergo apoptosis and in the case of neurons within the brain, this underlies the progressive nature of neurodegenerative diseases.

Mitochondria have long been implicated in the pathogenesis of neurodegenerative diseases as they are the neurons only source of cellular energy, ATP. In diseases such as GD and PD, these once vital organelles appear to become self-destructive, leaking damaging reactive oxygen species thus contributing to the overall pathogenesis of the disease. Therefore although the primary defect in GD is depletion of GCase in the lysosome, this impinges on the homeostasis of the whole cell due to defects in the autophagy pathway – in which the lysosome is a most vital player.

Our findings suggest that cellular dysfunction observed in GD, like that of PD, is a consequence of defects in autophagy/mitophagy pathways, resulting in failed clearance of damaged mitochondria. In addition we hope these observations provide further insight into consequences of impaired cellular quality control in relation to neurodegenerative disorders, and may help further illuminate the links between GD and PD.

Osellame, L., Rahim, A., Hargreaves, I., Gegg, M., Richard-Londt, A., Brandner, S., Waddington, S., Schapira, A., Duchen, M., 2013. Mitochondria and quality control defects in a mouse model of Gaucher disease--links to Parkinson’s disease. Cell Metab 17, 941–953.