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 inNeuron.