Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Sascha Martens, University of Vienna, Austria
- Second opponent: Associate Professor Åsa Birna Birgisdottir, The Arctic University of Norway - UiT, Norway
- Third member and chair of the evaluation committee: Professor Jason Matthews, University of Oslo
Chair of the Defence
Professor Erik Dissen, University of Oslo
Principal Supervisor
Professor Anne Simonsen, University of Oslo
Summary
Cells maintain homeostasis through autophagy, a pathway that carries out the removal of damaged or unwanted material and recycling of macromolecules under nutrient deprivation and stress. In autophagy, cargo is sequestered into double membrane vesicles known as autophagosomes that fuse with lysosomes containing enzymes that degrade the cargo. Autophagy can be a bulk degradation process or a selective one. Dysfunctional autophagy is implicated in the pathogenesis of many diseases, so elucidating its underlying molecular mechanisms is crucial for the development of new therapeutic strategies.
In this thesis, we aimed to identify proteins that are novel regulators of autophagy, characterise their function and investigate their roles in disease.
In paper I, we shortlisted protein candidates which bind membranes and have a link to disease, to assess whether they play a role in autophagy. Using a range of biochemical and imaging approaches, we demonstrated that the protein KRIT1 can interact directly with autophagy proteins. We also found that KRIT1 functions as a positive regulator of bulk and selective autophagy.
In paper II, we characterised another membrane binding protein, SYTL5. We found that SYTL5 localises to the mitochondrial network through an interaction with RAB27A. The selective degradation of mitochondria, through mitophagy, was found to be positively regulated by SYTL5 and RAB27A. We also found that SYTL5 expression is significantly reduced in adrenal gland tumours and that low SYTL5 expression is associated with reduced survival of adrenocortical carcinoma patients.
In paper III, we focus on the dipeptide repeat poly-GA protein aggregates that result from a mutation in C9orf72, associated with the neurodegenerative diseases ALS and frontotemporal dementia. We demonstrate that expression of poly-GA causes a reduction in autophagy, indicating a potential mechanism through which poly-GA aggregates contribute to neurodegeneration.
Additional information
Contact the research support staff.