- 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
In this paper Claudia Manzoni studies how fibroblast
cells from people with Parkinson’s disease caused by mutations in LRRK2
react to starvation. Although the changes are quite subtle, there are
differences between the way that fibroblasts that contain mutant LRRK2
respond to being starved – suggesting that there may be changes in the
way that these cells regulate a key process called autophagy (a term
which comes from the greek meaning to eat yourself, and is one of the
ways that cells get rid of waste and recycle proteins and organellles).
Research led by consortium researchers Dr Helene Plun-Favreau (UCL Institute of Neurology) and Dr Alex Whitworth (University of Sheffield), and collaborator Dr Heike Laman (University of Cambridge), has discovered how genetic mutations linked to Parkinson’s disease might play a key role in the death of brain cells, potentially paving the way for the development of more effective drug treatments. In the new study, published in Nature Neuroscience, the team of cross-institutional researchers showed how defects in the Parkinson’s gene Fbxo7 cause problems with mitophagy. More...
Mutations in LRRK2 are the most common genetic cause of Parkinson’s disease. Here, Claudia Manzoni talks about her research (funded by the Rosetrees Trust and the Michael J. Fox Foundation) into what LRRK2 might be doing within the cell: Parkinson’s disease is a brain illness that afflicts 1 in 500 people in the UK. High profile patients, such as the actor Michael J Fox, the boxer Muhammad Ali and the late Pope John Paul II, have raised public awareness of Parkinson’s and its devastating impact. More...
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. More...
First author Adamantios Mamais tells us about his recent publication in Neurobiology of Disease: At the Queen Square Brain Bank (part of the UCL Institute of Neurology) we hold a large collection of post-mortem human brain tissue from patients with neurodegenerative diseases including Parkinson’s disease (PD); a debilitating neurological disorder that affects the central nervous system. In the United States alone about 50,000 new cases are reported every year. The main symptoms include tremor, slow movement, rigid limbs and a shuffling gait while these worsen with time. More...
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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