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chromosome 22q deletion

Parkinson's chromosome deletion linked to other genetic disorders

Researchers, led by BRC-supported Professor Nicholas Wood, UCL Institute of Neurology, have made a breakthrough in their understanding of Parkinson’s disease after they discovered a chromosome deletion linked to Parkinson’s disease and other genetic disorders. More...

Prof John Hardy

Prof John Hardy is the first UK winner of $3m Breakthrough Prize in Life Sciences

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...

John Hardy, PhD, right, accepted the 2015 Robert A. Pritzker Prize from MJFF VP Brian Fiske, PhD, and Michael J. Fox on April 15.

John Hardy awarded 2015 Robert A. Pritzker Prize for Leadership in Parkinson's Research

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 - Prof Nicholas Wood - Advances in Genetic Understanding of Parkinson's Disease.

Video: Advances in Genetic Understanding of Parkinson's Disease

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...

Pedigrees and I-FP-CIT SPECT scan images of the four families with GCH1 mutations involved in this study.

GCH1 gene and Parkinson's risk

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.

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.

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