PhD ceremony Ms. A.T. van der Goot: Genetic modifiers of aging and age-related proteotoxicity

PhD ceremony: Ms. A.T. van der Goot, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Genetic modifiers of aging and age-related proteotoxicity

Promotor(s): prof. E.A.A. Nollen

Faculty: Medical Sciences

Neurodegenerative diseases, such as Alzheimer, Parkinson, and Huntington disease, are caused by the loss of neurons. Why neurons die is not clear yet but sticky disease proteins seem to play an important role. This is based on the finding that brains of patients contain accumulations of these proteins, also called aggregates. In healthy individuals, these aggregates are not present in such amounts. The aggregates contain disease-specific proteins. How these sticky proteins, or aggregation-prone disease proteins, cause neuronal toxicity, how they accumulate in aggregates, and how cells cope with such proteins is largely unknown.

Focus of the PhD study was to search for genes that can influence the formation and toxicity of protein aggregation in the small nematode C. elegans in which we modelled disease protein aggregation. The loss of at least two genes resulted in a reduction and a delay of toxicity of protein aggregation. These genes regulate the production of two proteins, namely of tryptophan 2,3-dioxygenase (TDO-2) and of modifier of aggregation 4 (MOAG-4). TDO-2 is essential for the degradation of the essential amino acid tryptophan, suggesting that tryptophan metabolism might play a role in toxicity caused by sticky disease proteins. In another study we found that MOAG-4 can enhance the formation of aggregates, most likely through a direct interaction with disease proteins. Together, these studies increased our understanding of how cells and organisms deal with protein damage. The genes that were indetified, provide interesting starting points for follow-up research for possible therapies to treat or delay neurodegenerative diseases.