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Project

Vision and peroxisomes: how does peroxisomal B-oxidation prevent retinal deterioration?

Vision is an intricate process that requires the optimal functioning of several highly specialized cell types and in which the retina plays an important role. The retina consists of different layers, such as the retinal pigment epithelium (RPE) and photoreceptors. The RPE is a single sheet of cells situated in between the photoreceptors and the choroidal blood supply. It plays a crucial role in photoreceptor survival by executing diverse tasks, such as the continuous isomerization and exchange of retinal with the photoreceptors and the phagocytosis of shed photoreceptor outer segments (POS).(1) Fatty acids containing more than 22 carbons, which are also present in the outer segments of the photoreceptors, depend on peroxisomal β-oxidation for their catabolism.(2-5)

Peroxisomes are extraordinary plastic compartments that adapt size, abundance and enzymatic content according to the cell type and the physiological/pathological circumstances.(6) Their particular role in each cell type is however still largely unknown. Peroxisomes are involved in redox metabolism and they play a prominent role in lipid metabolism, including the synthesis of ether lipids and the degradation of branched chain fatty acids by α- and β-oxidation. The latter pathway is also necessary for the breakdown of very long and dicarboxylic fatty acids, besides the aforementioned role in PUFA metabolism. Multifunctional protein 2 (MFP2) is a pivotal enzyme in peroxisomal β-oxidation as it handles both branched, unsaturated and very long carboxylates.(7-9)

We hypothesize that peroxisomal β-oxidation plays a crucial role in the maintenance of the retina by metabolizing lipid components of the retinal outer segments. Our knowledge on peroxisomal importance in the retina derives from histological descriptions several decades ago and from ophthalmological decay in peroxisomal diseases.(10-20) However, the precise role of the peroxisomal metabolism for the maintenance of the retina has never been thoroughly investigated. So we will define the function of peroxisomal β-oxidation in the retina.

The first aim is to characterize the structure and function of the retina in mouse models with global and cell type selective peroxisomal β-oxidation deficiency (Mfp2 knockout). This will be done using both invasive as non-invasive methods. The non-invasive techniques include electroretinogram (ERG) and spectral domain optical coherence tomography (OCT). Secondly, we will determine the lipidomic profile of the MFP2 deficient retina using at least one cutting edge approach: LC-MS/MS, applied on dissected retinas. The third aim is to investigate cellular and molecular deregulation. The emphasis will be on inflammation, redox imbalance and lipid droplet formation, depending on the histological and metabolic data. Finally, we will perform rescue experiments to restore MFP2 function by viral delivery as preclinical investigation. Therefore, viral vectors expressing MFP2 will be administered to the eye before, at onset and at midstage of the disease process. The best strategy for gene delivery is to do subretinal injections. To monitor the success of the therapy, we will take advantage of the non-invasive methods, complemented with histological evaluation at appropriate time points.

References

1. Sparrow, J. R. et al. Curr Mol Med 10, 802-823, (2010).

2. Anderson, D. M. et al. J Am Soc Mass Spectrom 25, 1394-1403, (2014).

3. McMahon, A. et al. Br J Ophthalmol 94, 1127-1132, (2010).

4. Noguer, M. T. et al. Invest Ophthalmol Vis Sci 51, 2277-2285, (2010).

5. Abe, Y. et al. Biochim Biophys Acta 1841, 610-619, (2014).

6. Islinger, M. et al. Biochim Biophys Acta 1803, 881-897, (2010).

7. Fransen, M. et al. Biochim Biophys Acta 1822, 1363-1373, (2012).

8. Van Veldhoven, P. P. J Lipid Res 51, 2863-2895, (2010).

9. Wanders, R. J. et al. Annu Rev Biochem 75, 295-332, (2006)

10. Robison, W. G., Jr. et al. Invest Ophtalmol 14, 866-872, (1975).

11. Leuenberger, P. M. et al. J Cell Biol 65, 324-334, (1975).

12. Beard, M. E. et al. Exp Eye Res 47, 795-806, (1988).

13.Zaki, M. S. et al. Hum Mutat 37, 170-174, (2016).

14. Lo, W. K. et al. Exp Eye Res 32, 1-10, (1981).

15. Majewski, J. et al. J Med Genet 48, 593-596, (2011).

16. Lambert, S. R. et al. Am J Ophthalmol 107, 624-631, (1989).

17. Ruether, K. et al. Surv Ophthalmol 55, 531-538, (2010).

18. Haugarvoll, K. et al. Orphanet J Rare Dis 8, 1, (2013).

19. Kobayashi, K. et al. Exp Eye Res 64, 719-726, (1997).

20. Ferdinandusse, S. et al. Ann Neurol 59, 92-104, (2006).

Date:6 Sep 2016  →  6 Sep 2020
Keywords:Eye, Retina, Peroxisomes, MFP2
Disciplines:Biomaterials engineering, Biological system engineering, Biomechanical engineering, Other (bio)medical engineering, Environmental engineering and biotechnology, Industrial biotechnology, Other biotechnology, bio-engineering and biosystem engineering, General biology, Plant biology, Laboratory medicine, Medical systems biology, Medicinal chemistry
Project type:PhD project