Neuroscience in Denmark


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General information

Name (center, department, group or other)
Dept. of Cellular and Molecular Medicine, PANUM, Copenhagen University
Contact name
Frederik Vilhardt
Contact email
vilhardt#at#sund#dot#ku#dot#dk
Contact title
Associate Professor, PhD
Date
17. December 2015


Brief description of research activities

The research of my group is contained within the triangulation field of microglia biology, membrane trafficking, and synucleinopathy.

In microglia, we are particularly interested in the superoxide-producing NADPH oxidase (NOX2), which is a major pathological promotor of neurodegeneration. When produced in excess, NOX2-derived oxidants confer oxidative stress and the direct oxidation of neuronal (and glial) macromolecules, which contributes to neuronal dysfunction and death. Moreover, NOX2-derived oxidants also control redox signaling in microglia, and is essential for the M1 activation of microglia and expression of many inflammatory functions of microglia. We are currently pursuing the identity of an intracellular agonist-regulated secretory compartment in microglia, which contains the major complement of NOX2. The storage compartment is dynamic, and agonist-regulated exocytosis/endocytosis cycles determines the surface expression of NOX2, which is particularly relevant to oxidative stress, as superoxide needs to be released directly to the external environment to participate in neurotoxic redox reactions.

A conceptual framework, which has attracted a lot of attention recently, is the ‘transmission hypothesis’ of neurodegenerative disease propagation in the brain. According to this theory malfolding disease (Parkinson, Alzheimer disease, amyotrophic lateral sclerosis and more) is propagated in a ‘prion-like’ manner, by the transmission of proteopathic aggregates (alpha-synuclein, amyloid-beta, or Tau) from affected to healthy neurons (or glia cells). We are interested in the release mechanisms of alpha-synuclein aggregate secretion, and we have recently shown in cellular models that exophagy, the exocytosis of autophagosomes, is a major mechanism of secretion. We have identified some protein factors that regulate this exocytosis, and we are currently defining the essential role of JNK3 in the process.

The transmission hypothesis does however not directly account for the requirement for microglia activation for disease propagation. We now know that inflammatory, but not surveying, microglia greatly increase alpha-synuclein secretion from dopaminergic neuronal cell lines in culture, and vice versa, the secretion of alpha-synuclein activates microglia. Although we have not specifically identified the microglial mediators that increase neuronal secretion of alpha-synuclein, we note that treatment of nerve cells in mono-culture with the classical pro-inflammatory cytokine TNF-alpha is sufficient to upregulate alpha-synuclein secretion through a JNK3-dependent mechanism. Our results indicate that reciprocal interactions between affected neurons and microglia may be necessary for propagation of disease.


Keywords

NADPH oxidase
Membrane trafficking
Microglia
Autophagy
Synucleinopathy
Neuroimmune communication

Research tools and techniques

Cell and Molecular Biological techniques
Biochemistry
Light and electron microscopy
Retroviral and lentiviral genetransduction

Scientific Personnel

No of Associate Professors/Postdocs: 1
No of PhD students: 0
Other: 2

Key references from within the last 5 years

1. Rasmussen, I., Vilhardt, F. Macropinocytosis is the entry mechanism of amphotropic murine leukemia virus. Journal of Virology, 89, 1851-66 (2015).
2. Ejlerskov, P., Rasmussen, I., Nielsen, T. T., Bergstrom, A. L., Tohyama, Y., Jensen, P. H., Vilhardt, F. Tubulin Polymerization Promoting Protein (TPPP/p25alpha) promotes unconventional secretion of alpha-synuclein through exophagy by impairing autophagosome-lysosome fusion. Journal of Biological Chemistry, 288, 17313 (2013).
3. Ejlerskov P, Christensen DP, Beyaie D, Burritt JB, Paclet MH, Gorlach A, van Deurs B, and Vilhardt F. NADPH Oxidase is Internalized by Clathrin-Coated Pits and Localizes to a Rab27A/B-Regulated Secretory Compartment in Activated Macrophages. Journal of Biological Chemistry, 287, 4835-52 (2012).
4. Hultqvist M, Sareila O, Vilhardt F, Norin U, Olsson LM, Olofsson P, Hellman U, Holmdahl R Positioning of a polymorphic quantitative trait nucleotide in the Ncf1 gene controlling oxidative burst response and arthritis severity in rats. Antioxidants and Redox Signaling, 14, 2373-832011, (2011).
5. Rasmussen, I., Pedersen, LH., Byg, L., Suzuki, K., Sumimoto, H., Vilhardt, F.: Effects of F/G-actin ratio and actin turn-over rate on NADPH oxidase activity in microglia. BMC Immunology, 11, 44, (2010).
Scherfigsvej 7
2100 Copenhagen Ø
Denmark
Tel. +45 39 12 80 00
CVR-nr. 11 81 49 13
info@thebrainprize.org
www.thebrainprize.org
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