By in vitro studies we try to approach fundamental unit operations in neuroinflammation and neurodegenerative disease with the aim of obtaining mechanistic insight.
The lab has a long-standing interest in NADPH oxidase (NOX2) trafficking and function in microglia (glia and macrophage cell of the CNS), and we would like to analyze in depth the molecular composition and function of the agonist-regulated secretory vesicles containing NADPH oxidase that we have identified.
By an exemplifying article we have recently introduced and substantiated the idea that proteotoxic a-synuclein aggregates, and in a wider perspective other amyloid species, are secreted from neurons by exophagy; the exocytosis of autophagosomes. Current work is aimed at understanding the bifurcature in the autophagsomal pathway, leading to either lysosomal degradation or secretion, and the localization and role of regulatory stress kinases JNK and p38MAPK.
Most recently we have shown that inflammatory, but not resting, microglia upregulate the secretion of a-synuclein species from dopaminergic neuron cell models through mechanisms that require microglia cytokine secretion and stimulation of neuronal stress kinases JNK2 and JNK3.
Current Project Areas
- NADPH Oxidase trafficking and function in microglia
- Stress kinases in a-synuclein autophagy and secretion from parkinsonergic neurons
- Uptake and processing of tau by microglia
- Synaptic dysfunction in models of Huntington Disease
- Trafficking defects in models of Huntington Disease
Haslund-Vinding J, McBean G, Jaquet V, and Vilhardt F. NADPH oxidases in Microglia oxidant production: Activating Receptors, Pharmacology, and Association with Disease. British Journal of Pharmacology 174, 1733-1749 (2017).
Ploug Christensen, D., Ejlerskov, P., Rasmussen, I., and Vilhardt F. Reciprocal signals between microglia and neurons regulate α-synuclein secretion by exophagy through a neuronal JNK signaling axis. Journal of Neuroinflammation 13, 59 (2016)
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).
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).
Cell Biology and Histology for students of Medicin and Molecular Biology, or Medicin and Technology and Quantitative Biology (different courses).
Supervision of ERASMUS and graduate students in the lab.
We are always underfunded but never outgunned. Current funding by:
- to whom we are greatly thankful.