VCP: An energy crisis in FTD?

Mutations in the VCP gene are a rare cause of FTD.  New work from UCL researchers suggests these mutations may lead to cell death by starving cells of the energy they require to function.

In recent years, it has become clear that even in clinically distinct disorders such as Alzheimer’s Disease and Parkinson’s Disease, there are common underlying themes in how the neurons become sick and die.  One such theme is a breakdown in the cells energy supply.

Mitochondria: The Cellular Power Stations

All cells, including neurons, rely on mitochondria for their energy supply.  In the same way as a power station takes coal, or nuclear fuel and converts it to electricity that we can use, mitochondria convert nutrients into a form of energy the cell can use (called ATP), by a process called respiration.

The VCP protein already had a known role in mitochondrial maintenance, helping to remove damaged mitochondria from the cell.  In their current work, the researchers wanted to investigate the idea that mutations in VCP could lead to cellular damage by affecting mitochondrial function.

In order to do this, lead author Fernando Bartolome-Robledo measured mitochondrial activity in fibroblasts (skin cells) derived from patients carrying disease-causing mutations in the VCP gene.  What he found was striking:  the amount of oxygen consumed by the mitochondria was dramatically increased, but the amount of energy, or ATP, produced was significantly decreased.   These two processes are normally tightly coupled, i.e. consuming more oxygen should allow the mitochondria to produce increased levels of ATP.  This uncoupling and decreased ATP production means that the cells cannot produce enough ATP to cope with energy-demanding processes, and will render the cells more vulnerable to other cellular stresses such as oxidative stress, or removing protein aggregates that are a common feature of diseases including FTD.

To be confident that this was a true effect of VCP dysfunction, the authors repeated their findings in neuronal cells with VCP removed, and in neuronal cells artificially expressing the mutated forms of VCP.  In all cases the results were in agreement: VCP mutations reduce mitochondrial efficiency.

Further support for the role of VCP in mitochondrial function comes from a second publication, using fruit flies to study VCP function.  Kim and colleagues found that VCP acts in concert with several other proteins to remove damaged mitochondria. Thus, VCP dysfunction could lead to an accumulation of damaged mitochondria that are unable to produce energy efficiently, as shown by Bartolome and colleagues.  Interestingly, the other proteins in this pathway, PINK1 and Parkin, are known to be involved in Parkinson’s disease pathogenesis, pointing at common pathways linking several diseases.

What does this mean for FTD?

It is important to remember that these are early-stage findings: the next steps are to extend this work in order to understand the precise steps by which VCP mutations lead to mitochondrial breakdown, and why genetic alterations in VCP can lead to several clinically distinct neurodegenerative disorders.  Nonetheless, this is very exciting news for FTD as it represents a previously unknown link between VCP dysfunction and mitochondrial dysfunction, that could ultimately lead to cell death.  The identification of drugs that prevent this mitochondrial dysfunction could help in the treatment of diseases such as FTD.

References

Bartolome F, Wu HC, Burchell VS, Preza E, Wray S, Mahoney CJ, Fox NC, Calvo A, Canosa A, Moglia C, Mandrioli J, Chiò A, Orrell RW, Houlden H, Hardy J, Abramov AY, Plun-Favreau H. Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels. Neuron. 2013;78(1):57-64.

Kim NC, Tresse E, Kolaitis RM, Molliex A, Thomas RE, Alami NH, Wang B, Joshi A, Smith RB, Ritson GP, Winborn BJ, Moore J, Lee JY, Yao TP, Pallanck L, Kundu M, Taylor JP. VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations. Neuron. 2013;78(1):65-80.

Comments are closed.