Dr Kurt De Vos
Lecturer in Translational Neuroscience
Department of Neuroscience
Sheffield Institute for Translational Neuroscience
& Centre for Membrane Interactions and Dynamics
University of Sheffield
385a Glossop Road
Tel: +44 (0)114 2222241
Secretary: Bev Carter
Tel: + 44 (0)114 2222295
- 2011-present Lecturer in Translational Neuroscience
- 2006-2011 Senior Researcher, MRC Centre for Neurodegeneration Research, The Institute of Psychiatry, King's College London, London, UK.
- 2004-2006 Postdoctoral Researcher, Academic Unit of Neurology, The University of Sheffield, Sheffield, UK.
- 2003-2004 Postdoctoral Researcher/Visiting Scientist, School of Biological Sciences, University of Manchester, Manchester, UK.
- 2000-2003 Postdoctoral Researcher, Department of Biological Sciences, Columbia University, New York, USA.
- 1994-1999 PhD in Science: Biotechnology (Greatest distinction), University of Ghent, Ghent, Belgium.
Dr De Vos studied chemistry and biotechnology and received a PhD in Biotechnology with greatest distinction from Ghent University, Belgium (1999; advisor Prof Johan Grooten). There he showed that clustering of mitochondria in the perinuclear region is an early event in apoptosis that is caused by inhibition of the molecular motor kinesin through hyperphosphorylation of the kinesin light chain (De Vos et al., 1998; De Vos et al., 2000).
He then embarked on his postdoctoral research work in the laboratories of Prof Mike Sheetz at Columbia University, New York, and Dr Vicky Allan at the University of Manchester. There he showed that phosphatidyl inositol phosphates control the direction of axonal mitochondrial transport (De Vos et al., 2003). In addition he established that mitochondrial function controls mitochondrial dynamics and showed that the actin cytoskeleton is required for the recruitment of mitochondrial fission factor DRP1 to mitochondria (De Vos et al., 2005).
He became particularly interested in mitochondrial dynamics and neurodegeneration and relocated to the University of Sheffield to work in Dr Andy Grierson’s laboratory. There his research was focused on motor neuron diseases and the characterisation of mitochondrial axonal transport defects in models of amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (De Vos et al., 2007; Kasher et al., 2009). This work was continued in the laboratory of Prof Chris Miller and Prof Chris Shaw in the MRC Centre for Neurodegeneration Research at King’s College London, and resulted in publications showing that VAPB interacts with mitochondrial protein PTPIP51 and that ALS VAPBP56S the disrupts axonal transport of mitochondria by increasing intracellular calcium levels.
End of 2011 he returned to Sheffield and took up the post of Lecturer in Translational Neuroscience in the newly established Sheffield Institute for Translational Neuroscience (SITRaN).
Research in the laboratory focuses on the mechanisms of nerve cell death in amyotrophic lateral sclerosis (ALS; also known as motor neuron disease (MND) or Lou Gehrig disease), hereditary spastic paraplegia (HSP) and Parkinson’s disease (PD). We are especially interested in the involvement of axonal transport, mitochondria and ER.
Current research themes include:
- The mechanisms causing defective axonal transport of mitochondria in ALS, PD and HSP.
- The cellular roles of C9ORF72 protein and their role in ALS and FTD
- The biology of close contacts between the endoplasmic reticulum (ER) and mitochondria and their involvement in health and disease
Work in the lab is funded by grants from the Medical Research Council (MRC), the Thierry Latran Foundation, the Motor Neurone Disease Association (MNDA), the Spastic Paraplegia Foundation, and the Moody Endowment Fund.
- Anne-Kathrin Möller (Postdoctoral Research Associate)
- Chris Webster (PhD Student)
- Emma Smith (Research Assistant)
- Gary Shaw (Research Assistant)
- Natalie Rounding (PhD Student)
- Yolanda Gibson (PhD Student)
- Richard Lucas (PhD student)
- Khlood Mehdar (PhD Student)
- Claudia Bauer (postdoc)
- Emma Wilson (PhD student)
- Becky Cohen (PhD student)
- Medical Research Council (MRC)
- Thierry Latran foundation
- UK Motor Neurone Disease Association
- Moody endowment fund
Neurons are specialised cells in the brain and spinal cord that transmit nerve impulses (e.g. impulses of sensation to the brain, or impulses from the brain to muscles and organs). Neurons comprise cell bodies and long threadlike processes that extend away from the cell body. These processes are called axons and dendrites. Axons conduct impulses from the neuron cell body to other cells. In the brain, the end of the axon, called the synapse, connects to other neurons so as to mediate the brain’s computing power. In the spinal cord, motor neuron axons connect to muscle cells to facilitate muscle contraction. Axons of motor neurons can be longer than 1 meter!
Most of the proteins present in axons are produced in the cell body and are carried into and through the axon by a process called axonal transport. Molecular motor proteins drive axonal transport. These motors burn a fuel called ATP to generate locomotive force and run on protein tracks called microtubules. Thus, axonal transport is rather like a train journey with “locomotives” (molecular motors) that need “fuel” (ATP), run on “rails” (microtubules) and hook up to various “carriages” (cargoes). The components of axonal transport are shown in Figure 1.
Axonal transport of proteins and organelles is essential for proper neuron function and viability. When axonal transport malfunctions the axon slowly starves because the necessary proteins and other nutrients (e.g. ATP) are no longer delivered. The regions of the axon that are the furthest away from the cell body (motor neuron axons can be over a metre in length!) are most severely affected by axonal transport failure; these far-off axonal regions degenerate and die off, and as a result the connection between neurons and their targets is lost. Importantly, this is in fact what is observed in neurodegenerative diseases such as ALS.
Figure 1: Axonal transport. Axonal transport of cargoes such as mitochondria is mediated by molecular motors (“Locomotives”) that run on microtubules (“Rails”). Kinesin molecular motors move toward the plus-end of microtubules and mediate transport toward the synapse. Cytoplasmic dynein moves toward the minus-end of the microtubule and mediates transport back to the cell body.
We now know that axonal transport malfunctions in a number of neurodegenerative diseases including ALS, HSP and PD (De Vos et al., 2007; Kasher et al., 2009). We also know that axonal transport malfunction is one of the earliest, and possibly the earliest defect in these diseases. Therefore, understanding how healthy axonal transport works and what causes it to malfunction in these diseases is very important and is likely to reveal novel drug targets that may be developed into medicines aimed at sufferers from these diseases.
Figure 2: Measuring axonal transport. Neurons grown in culture on a coverslip (to panel) are transfected with green fluorescent protein (GFP) to visualize the axon and red fluorescent protein targeted to mitochondria to visualize mitochondria. Thus transfected neurons are put on a microscope and the movement of mitochondria is recorded. Movies of mitochondrial movements are converted into a kymograph to visualize movement.
Current projects in the lab investigate the molecular mechanisms of axonal transport defects in ALS, HSP and PD, and test novel drugs aimed at restoring axonal transport.
The cellular role of C9ORF72 protein and its role in ALS
Expansions of a noncoding GGGGCC hexanucleotide repeat in the C9ORF72 gene are the most common genetic defect found to date in familial ALS and frontotemporal dementia (FTD). It is also the strongest genetic risk factor for sporadic ALS. How these expansions cause disease is not known, but may involve both loss-of-function (C9ORF72 haploinsufficiency), and gain-of-function (repeat-associated non-ATG (RAN) translation, RNA toxicity) mechanisms. The C9ORF72 gene encodes an uncharacterised protein that is highly conserved in vertebrates, indicating that its function is likely to be important.
Current projects aim to understand the cellular functions of the C9ORF72 protein. We have identified a number of candidate proteins that interact with C9ORF72 and are characterising their association with C9ORF72 and their possible role in ALS/FTD.
Mitochondria-associated ER membranes (MAM)
Mitochondria-associated ER membranes (MAM) are specialized domains of the endoplasmic reticulum (ER) that are in physical contact with mitochondria. Between 5 and 20% of the mitochondrial surface is closely apposed to MAM membranes. Through these close contacts, mitochondria and ER communicate directly with each other via the exchange of calcium signals. Under physiological conditions, mitochondrial calcium activates the rate-limiting enzymes of the Krebs cycle and thereby increases oxidative phosphorylation and ATP synthesis to match local energy demand. In turn, energized mitochondria influence ER calcium homeostasis and redox dependent ER processes such as oxidative protein folding. In agreement with an essential cellular function of ER-mitochondria communication, dysfunctional signalling between ER and mitochondria has been linked to neurodegenerative diseases, diabetes, cancer and inflammation.
Figure 3: Visualization of MAM by transmission electron microscopy. Mitochondria a labeled with “M”.
A large body of evidence implicates ER stress and damage to mitochondria in the pathogenesis of both familial and sporadic ALS. However, the upstream causes of ER stress or mitochondrial damage remain to be determined. How mutations in non-ER and non-mitochondrial proteins that cause ALS elicit ER stress and mitochondrial dysfunction is a conundrum and the mechanisms linking these apparently disparate insults with other ALS-associated pathologies such as cytosolic TDP43 accumulation and defects in axonal transport are unclear.
Our data suggests that a possible explanation lies in dysfunctional signalling at MAM. We have shown in two publications that MAM is implicated in familial ALS caused by a mutation in VAPB (VAPBP56S). We found that perturbation of MAM by VAPBP56S causes mitochondrial dysfunction by calcium overload and as a consequence disturbs calcium homeostasis (De Vos et al., 2012). This in turn causes a permanent increase in cytosolic calcium levels, which is directly responsible for the inhibition of anterograde transport of mitochondria in VAPBP56S-expressing neurons (De Vos et al., 2012; Morotz et al., 2012)(see above axonal transport). Thus, our data shows that damage to inter-organelle signalling at the ER-mitochondria interface is upstream of a number of ALS-associated toxicity pathways including mitochondrial dysfunction, disturbance of calcium homeostasis, and defective axonal transport.
Figure 4: VAPBP56S disrupts axonal transport. VAPBP56S increases interaction of ER and mitochondria via PTPIP51. This leads to calcium overload in mitochondria and an increase in cytosolic calcium levels. Increased cytosolic calcium binds to Miro1 and inhibits kinesin-mediated anterograde transport of mitochondria.
Current projects further investigate these findings and extend these studies to other models of ALS to establish if compromised MAM and defective signalling between ER and mitochondria is a common phenomenon in ALS and a possible therapeutic target.
- Chapman, A.L., et al., Axonal Transport Defects in a Mitofusin 2 Loss of Function Model of Charcot-Marie-Tooth Disease in Zebrafish. PLoS One, 2013. 8(6): p. e67276.
- Morotz, G.M., et al., Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria. Hum Mol Genet, 2012. 21(9): p. 1979-88.
- De Vos, K.J., et al., VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum Mol Genet, 2012. 21(6): p. 1299-311.
- Vagnoni, A., et al., Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1. Journal of Cell Science, 2011. 124(Pt 7): p. 1032-1042.
- Sargsyan, S.A., et al., A comparison of in vitro properties of resting SOD1 transgenic microglia reveals evidence of reduced neuroprotective function. BMC neuroscience, 2011. 12(1): p. 91.
- Manser, C., et al., Lemur tyrosine kinase-2 signalling regulates kinesin-1 light chain-2 phosphorylation and binding of Smad2 cargo. Oncogene, 2011: p. -.
- Tudor, E.L., et al., Amyotrophic lateral sclerosis mutant VAPB transgenic mice develop TDP-43 pathology. Neuroscience, 2010.
- Gray, E.H., et al., Deficiency of the copper chaperone for superoxide dismutase increases amyloid-β production. Journal of Alzheimer's disease : JAD, 2010. 21(4): p. 1101-1105.
- Yates, D.M., et al., Neurofilament subunit (NFL) head domain phosphorylation regulates axonal transport of neurofilaments. European journal of cell biology, 2009. 88(4): p. 193-202.
- Vance, C., et al., Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6. Science (New York, NY), 2009. 323(5918): p. 1208-1211.
- Stevenson, A., et al., Riluzole protects against glutamate-induced slowing of neurofilament axonal transport. Neuroscience Letters, 2009. 454(2): p. 161-164.
- Kasher, P.R., et al., Direct evidence for axonal transport defects in a novel mouse model of mutant spastin-induced hereditary spastic paraplegia (HSP) and human HSP patients. Journal of Neurochemistry, 2009. 110(1): p. 34-44.
- De Vos, K.J., et al., Role of axonal transport in neurodegenerative diseases. Annual review of neuroscience, 2008. 31: p. 151-173.
- De Vos, K.J. and M.P. Sheetz, Visualization and quantification of mitochondrial dynamics in living animal cells. Methods in cell biology, 2007. 80: p. 627-682.
- De Vos, K.J., et al., Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. Human molecular genetics, 2007. 16(22): p. 2720-2728.