- Prof John Hardy is the first UK winner of $3m Breakthrough Prize in Life Sciences
- John Hardy awarded 2015 Robert A. Pritzker Prize for Leadership in Parkinson's Research
- Video: Advances in Genetic Understanding of Parkinson's Disease
- GCH1 gene and Parkinson's risk
- The new Leonard Wolfson Experimental Neurology Centre (LWENC) has opened for clinical studies and trials
- LRRK2 and autophagy in fibroblasts
- LRRK2 and autophagy
- GBA and mitochondria
- Alpha-synuclein in LRRK2 brains
- α-Synucleinopathy associated with G51D SNCA mutation: A link between Parkinson’s disease and multiple system atrophy?
- Video: Parkinson's and the Genetic Revolution: From Genes to Treatments
- Public lecture: The autophagy signaling network, c-‐myc and pathology: don't mess with the cell cycle!
- Video: Brain Disease Research - Keeping You You
- Video: Degenerating Brains public symposium
- Mutations in VCP gene implicated in a number of neurodegenerative diseases
- Public lectures: new research into Alzheimer's, Parkinson's and Motor Neuron Disease
- Blog: Degenerating neurons
- Global research team discovers new Alzheimer’s risk gene
- Direct Observation of the Interconversion of Normal and Toxic Forms of a-Synuclein
- Video: The genetics of LRRK2 by Nick Wood
- Video: Parkinson's UK site visit for the Targeting LRRK2 project
- Successes of Deep Brain Stimulation for patients with Parkinson's disease
- Recordings in Parkinson's disease patients reveal details of communication between deep and superficial brain structures
- Five new Parkinson's genes identified
Professor John Hardy (UCL Institute of Neurology) has been awarded the $3 million Breakthrough Prize in Life Sciences for his pioneering research into the genetic causes of Alzheimer’s disease, other forms of dementia and Parkinson’s disease. More...
One of the UK Parkinson's Disease Consortium Principal Investigators, Prof John Hardy, has been awarded the 2015 Robert A. Pritzker Prize for his leadership in Parkinson's genetics research. The award was presented by Michael J. Fox at a ceremony in New York on April 15. From the Michael J. Fox Foundation website: More...
Webcast of the presentation entitled ‘Advances in Genetic Understanding of Parkinson's Disease’ given by Nicholas Wood (University College London, United Kingdom) presented at the Biochemical Society Hot Topic event, PINK1-Parkin Signalling in Parkinson’s Disease and Beyond, held in December 2014. More...
A study published in Brain, led by researchers
at UCL Institute of Neurology, has shown that genetic mutations which
cause a decrease in dopamine
production in the brain and lead to a form of childhood-onset Dystonia,
also play a role in the development of Parkinson’s disease.
The new Leonard Wolfson Experimental Neurology Centre (LWENC) has opened for clinical studies and trials
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.
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.
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