28.10. Regulation of retinal protein aggregates – key to treatment of age-related macular degeneration?

Public examination of a doctoral dissertation in the field of ophthalmology

Doctoral candidate MSc Tuomas Ryhänen

Time and venue: 28.10.2011 at 12 noon, Mediteknia Auditorium, Kuopio Campus

Age-related macular degeneration (AMD) is a progressive neurodegenerative eye-disease that is the most common reason for visual impairment in western countries. The number of people suffering from AMD is constantly growing. Currently, there is no treatment available for the vast majority of AMD patients and the pathological mechanisms at the molecular level are not well understood. Retinal pigment epithelial cells (RPE) and different extra- and intracellular protein aggregates play a significant role in the development of this disease. Several beneficial and protective cellular systems, such as heat shock protein (Hsp) response and proteolysis, deteriorate in aged RPE cells. In time, this leads to degeneration in photoreceptors and subsequently to severe difficulties in vision.

In the present series of studies, lipid peroxidation product 4-hydroxy-2-nonenal (HNE)-induced oxidative stress was first studied with Hsp70 inducer (Hsp90 inhibitor), followed by the characterisation of two different Hsp90 inhibitors. Subsequently, protein aggregation and its possible removal processes and their links to Hsp70 were examined. In the fourth study, the roles of Hsp90, microtubule network and its acetylation were assessed in the formation and degradation of protein aggregates. All studies were conducted with a human RPE cell line (ARPE-19).

Hsp70 and Hsp90 are involved in the regulation of HNE-induced oxidative stress reaction. Although the Hsp90 inhibitor increased the level of Hsp70 significantly, it potentiated the HNE-induced cell death. Interestingly, the non-quinone Hsp90 inhibitor, radicicol, induced more oxidative stress than the quinone geldanamycin, and furthermore geldanamycin was found to be more toxic. Proteasome inhibitor-induced protein aggregates were demonstrated to be lysosomal and positive for Hsp70 and ubiquitin. Hsp70 and especially Hsp90 were shown to regulate the formation of protein aggregates with the microtubule network playing an important role. It seems that at least non-senescent RPE cells have the capacity to degrade protein aggregates. This was observed to occur via autophagic degradation and it appears that molecular chaperone Hsp70 is involved in this process.

In conclusion, these findings clarify the protein aggregation process in RPE cells. In addition, the already known significant role of Hsps in cellular survival was amplified. The results presented in this dissertation contribute to the overall knowledge on the function of RPE cells and provide a new target for designing novel therapies against AMD and other age-related degenerative protein aggregation diseases.

The doctoral dissertation of Master of Science Tuomas Ryhänen, entitled Crosstalk between Molecular Chaperones, Protein Aggregation and Autophagic Degradation in Retinal Pigment Epithelial Cells: Implications for the Pathogenesis of Age-Related Macular Degeneration will be examined at the Faculty of Health Sciences. The opponent in the public examination will be Professor Arto Urtti of the University of Helsinki and the custos will be Professor Kai Kaarniranta of the University of Eastern Finland.

Photo available for download at http://www.uef.fi/vaitoskuvat.

Publishing year: 2011

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