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Leonard Wolfson Experimental Neurology Centre (LWENC)

The new Leonard Wolfson Experimental Neurology Centre (LWENC) has opened for clinical studies and trials

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Audioslide presentation on Claudia Manzoni's paper examining how fibroblasts with LRRK2 mutations react to starvation conditions and the possible deficits that they have in autophagy.

LRRK2 and autophagy in fibroblasts

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).
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Drosophila fly model - University of Sheffield

Genetic mutations linked to Parkinson's disease

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...

Autophagy

LRRK2 and autophagy

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...

GBA neurons

GBA and mitochondria

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...

Mutations in VCP gene implicated in a number of neurodegenerative diseases

20 March 2013

Colour-enhanced image of a mitochondrion showing the internal membranes (cristae) and enzyme complexes. Credit Dr David Furness, Wellcome Images.

New research, published in Neuron, gives insight into how single mutations in the VCP gene cause a range of neurological conditions including a form of dementia called Inclusion Body Myopathy, Paget’s Disease of the Bone and Frontotemporal Dementia (IBMPFD), and the motor neuron disease Amyotrophic Lateral Sclerosis (ALS).

Single mutations in one gene rarely cause such different diseases. This study shows that these mutations disrupt energy production in cells shedding new light on the role of VCP in these multiple disorders.

In healthy cells VCP helps remove damaged mitochondria, the energy-producing engines of cells. The mutant protein can’t do this and as a result, the dysfunctional mitochondria build up.

The new study led by Dr Fernando Bartolome, Dr Helene Plun-Favreau and Dr Andrey Abramov of the UCL Institute of Neurology, found that mitochondria are damaged in cells from patients with mutant VCP. Mitochondria generate a cell’s energy, and the study found these damaged mitochondria are less efficient, burning more nutrients but producing less energy. This reduction in available energy makes cells more vulnerable, which could explain why mutations in the VCP gene lead to neurological disorders.

Lead author Dr Fernando Bartolome said, “We have found that VCP mutations are associated with mitochondrial dysfunction. VCP had previously been shown to be important in the removal of damaged mitochondria and proteins, accumulation of which is potentially very toxic to cells. A single mutation in the VCP gene could cause multiple neurological diseases because a different type of protein is accumulating in each disorder”.

In the study, the researchers used live imaging techniques to examine the functioning of mitochondria in patient cells carrying three independent VCP mutations, and in nerve cells in which the amount of VCP has been reduced.

“The next step will be to find small molecules able to correct the mitochondrial dysfunction in the VCP deficient cells”, added Dr Bartolome.

Dr Brian Dickie, the Motor Neuron Disease Association’s Director of Research Development says: “Neurons - and motor neurons in particular - are incredibly energy hungry cells. These new findings from the team at UCL show that there is a significant interruption of energy supply in this hereditary form of MND, which has strong implications for understanding the degenerative process underpinning all forms of the disease.”

The research was supported in part by a Wellcome Trust/MRC Joint Call in Neurodegeneration award and by the Spanish Ministerio de Educación through the Fundación Española para la ciencia y la tecnología (FECYT) and grants from the ALS Association and Motor Neuron Disease (MND) Association.

Fernando Bartolome, Hsiu-Chuan Wu, Victoria S. Burchell, Elisavet Preza, Selina Wray, Colin J. Mahoney, Nick C. Fox, Andrea Calvo, Antonio Canosa, Cristina Moglia, Jessica Mandrioli, Adriano Chiò, Richard W. Orrell, Henry Houlden, John Hardy, Andrey Y. Abramov, Helene Plun-Favreau. Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels. Neuron, 2013; DOI: 10.1016/j.neuron.2013.02.028

Page last modified on 20 mar 13 13:44