Mutations in VCP gene implicated in a number of neurodegenerative diseases

14 March 2013

Mitochondrion

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

New research 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. 

Dr 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 said: "Neurons, and motor neurons in particular, are incredibly energy hungry cells. These new findings 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 work was carried out in collaboration with scientists from the University of Turin and the S. Agostino-Estense Hospital and University of Modena in Italy. The paper, Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels, is published in Neuron.

  • Single mutations in a gene called VCP, which stands for valosin-containing protein, can cause a number of different neurodegenerative diseases, according to new research from UCL. It's rare for single mutations in one gene to cause such different diseases.
  • In healthy cells the enzyme coded for by the VCP gene helps remove damaged mitochondria, the energy-producing engines of cells. When the enzyme is damaged due to these single gene mutations, it can no longer remove dysfunctional mitochondria, which build up in the cell reducing the amount of energy available.
  • The scientists speculate that the single mutations in VCP might cause different diseases by allowing a different toxic protein to accumulate in each disease.