Age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), are an increasing burden on society. While immune signaling contributes to the pathogenesis of these diseases, the nature of the immune genes involved is largely unknown. We aim to identify immune genes that contribute to the pathogenesis of neurodegenerative diseases and to alleviate symptoms by manipulating the activity of these genes.
neurology, immunology, genetics
- Snijder PM, Baratashvili M,, Leuvenink HGD, Kuijpers L, Huitema S, Giepmans BNG, KuipersJ, Miljkovic JL, Mitrovic A, Bos EM, Szabó C, Kampinga H, Dijkers PF, Den Dunnen WFA, Filipovic MR, Van Goor H, Sibon OCM (2015). Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3. Mol. Med. 758-768. (pdf)
- Li YX, Dijkers PF. (2015) Specific calcineurin isoforms are involved in Drosophila toll immune signaling. Immunology 2015 194 (1):168-76. (pdf)
- Dijkers, P.F., and O’Farrell, P.H. Dissection of a hypoxia-induced, nitric oxide-mediated signaling cascade. (2009) Mol Biol Cell. 18: 4083-90. (pdf)
- Dijkers, P.F., and O’Farrell, P.H. Drosophila Calcineurin promotes induction of innate immune responses. (2007) Biol. 17: 2087-2093. (pdf)
- Rosas M., Dijkers P.F., Lindemans C.L., Lammers J.W., Koenderman L., Coffer P.J. (2006) IL-5-mediated eosinophil survival requires inhibition of GSK-3 and correlates with beta-catenin relocalization. Leukoc Biol. 80(1):186-95. (pdf)
- Van den Heuvel A.P., de Vries-Smits A.M., van Weeren P.C., Dijkers P.F., de Bruyn K.M., Riedl J.A., Burgering B.M..(2002) Binding of protein kinase B to the plakin family member periplakin. J Cell Sci. 115(Pt 20):3957-66. (pdf)
- Dijkers P.F. Birkenkamp K.U., Lam E.W., Thomas N.S., Lammers J.W., Koenderman L., Coffer P.J. (2002) FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity J Cell Biol. 156(3):531-42. (pdf)
- Stahl M., Dijkers P.F., Kops G.J., Lens S.M., Coffer P.J., Burgering B.M., Medema R.H. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. (2002) J Immunol. 168(10):5024-31. (pdf)
- Kops G.J., Medema R.H., Glassford J., Essers M.A., Dijkers P.F., Coffer P.J., Lam E.W., Burgering B.M.. 2002 Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors. Mol Cell Biol. 22(7):2025-36. (pdf)
- Dijkers, P.F. (2001) Molecular mechanisms of cytokine-mediated proliferation and survival, doctoral thesis, University Medical Center, Utrecht, The Netherlands. (pdf)
- Dijkers, P.F., Medema, R.H., Lammers, J-W.J., Koenderman, L. and Coffer, P.J. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the Forkhead transcription factor FKHR-L1. (2000) Biol. 10, 1201-1204. (pdf)
- Dijkers P.F., Medema R.H., Pals C., Banerji L., Thomas N.S., Lam E.W., Burgering B.M., Raaijmakers J.A., Lammers J.W., Koenderman L., Coffer P.J. Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27. (2000) Cell. Biol. 20(24):9138-48. (pdf)
- Geijsen, N., Dijkers, P.F., Lammers, J-W.J., Koenderman,L. and Coffer, P.J. Cytokine-mediated cPLA2 phosphorylation is regulated by multiple MAPK family members. (1999) FEBS Letts. 471, 83-8. (pdf)
- Dijkers, P.F., van Dijk, T.B., de Groot, R.P., Raaijmakers, J.A.M., Lammers, J-W.J., Koenderman, L. and Coffer, P.J. Regulation and function of Protein Kinase B and MAP kinase activation by the IL-5/IL-3/GM-CSF receptor. (1999) Oncogene 18, 3334-334. (pdf)
We focus on two neurodegenerative disease models:
- Spinocerebellar Ataxia 3 (SCA3) : a polyQ disease. PolyQ diseases are dominantly inherited diseases, and are caused by an expansion in the glutamine stretch in a particular gene, in SCA3 the ATXN3 gene. This expansion of glutamines results in misfolding of the protein and its accumulation in toxic aggregates. These expanded proteins are particularly toxic in neurons, resulting in neurodegeneration.
- Alzheimer’s disease: extracellular aggregates of Abeta peptides are found in brains of patients. These peptides are neurotoxic.
We have carried out a genetic screen for modifiers of the SCA3 phenotype in Drosophila (fruit flies), using expression of human expanded SCA3 in the Drosophila eye. We examined whether the SCA3 eye phenotype could be modified upon RNA interference targeting immune genes in (1) brain-resident immune cells (astrocytes and microglia) and (2) peripheral immune cells. We are further analyzing the identified in the screen (both enhancers of suppressors of SCA3) and testing them in the Alzheimer’s disease model.
Figure Identification of immune genes involved in neurodegeneration. Expression of expanded SCA3 (SCA3 78Q) in Drosophila eyes results in a degenerative phenotype. We identified enhancers as well as suppressors of this phenotype, using RNA interference in immune cells.
Microglia contribute to the pathogenesis of AD, gene signatures in microglia of AD models have been identified. We are currently testing the relevance of these genes in our AD model, where abeta peptides are expressed in the brain, and perform RNAi against these genes in microglia.
Pascale Dijkers studied Medical Biology at the University of Utrecht, The Netherlands. She obtained her PhD in 2001, working in the laboratory of Prof. Paul Coffer (Utrecht University). There, she studied how signaling in immune cells can prevent apoptosis.
Subsequently, Dijkers moved to the laboratory of Prof. Pat O’Farrell at the University of California, San Francisco, US, to study signaling in the context of an organism. Here, she started working with Drosophila (fruit flies), a powerful model organism for studying medically relevant topics in humans. She studied signaling in response to low oxygen (hypoxia) and innate immune signaling.
In 2012, Dijkers was appointed as a Rosalind Franklin Fellow at the University of Groningen where she is studying the role of immune signaling in neurodegenerative diseases.
- Analysis of involvemenent of brain-resident immune cells in neurodegeneration
This project aims to further characterize the genes identified in the screen in brain-resident immune cells, attempting to answer the questions:
1. What is the molecular mechanism by which the gene can exert its effect? To answer this, we will use a combination of immunohistochemical techniques (examining neurons), cell culture and molecular biology.
2. What is the effect of these genes in the Alzheimer model?
- Analysis of involvemenent of peripheral immune cells in neurodegeneration
While there is an overlap between genes that affect the SCA3 phenotype in brain-resident immune cells versus peripheral immune cells, there are also differences. This project aims to further genes identified in the screen in peripheral immune cells, addressing similar questions as in project 1.Techniques:
Drosophila genetics, cell biological techniques (immunohistochemistry), biochemical techniques (western blotting), molecular biology (QPCR, cloning), cell culture (transfection).
You can apply via this application form.