Characterization of the impact of proteins linked to neurodegenerative diseases in the yeast Saccharomyces cerevisiae

Our society will have to face an estimated of about 65 million cases of dementia in 2030 and 115 million cases by the year 2050. Alzheimer's Disease represents the majority of these cases. Despite tremendous efforts of the research community to unravel the disease mechanisms, there is still a lack of insight in disease pathogenesis. This disorder is substantially heterogeneous, both at the level of genetics as well as at the level of clinical and neuropathological presentation.

The aim of this thesis was to investigate the impact of proteins involved in neurodegenerative diseases, especially Aβ, α-Synuclein and tau, on cellular processes. Neurodegenerative Diseases, such as Alzheimer's, or Parkinson's disease, are complex, multifactorial pathologies. Over the last decades, large efforts have been made to pinpoint the causative mechanisms and to develop effective treatments against these diseases. However, these aims have not been reached yet, and although progress has been made in understanding some aspects of the disease onset and progression, the underlying mechanisms of Alzheimer's and Parkinson's disease are still not known, and there are no potent treatments available today.

To shed light on these issues, firstly, a yeast model was created to study the impact of Aβ on biochemical pathways and intracellular organelles. By making use of clinical as well as synthetic Aβ mutants, not only previous reports that Aβ acts on mitochondria to induce cellular stress could be confirmed, but it could be also demonstrated that it impairs vesicular trafficking and membrane repair events. The Endosomal Sorting Complex Required for Transport (ESCRT) factor Bro1 was identified to be crucial for this process. Furthermore, toxic Aβ species disturb the lipid metabolism and lead to the aggregation of the endoplasmic reticulum.
In collaboration with Roel Van Assche, who expressed Aβ and tau in C. elegans, and subsequently performed metabolomics, the kynurenine pathway has been identified as a potential link to Aβ-toxicity. The kynurenine-factor Bna1 seems to play a crucial role in mediating Aβ-toxicity and modulating synergistic effects between Aβ and tau or α-Synuclein in yeast.
Previous studies suggest, that the microtubule-binding K18-domain of tau has a propensity to aggregate. Here, we modulated, optimized, and characterized yeast-based prion-detection systems for further investigation of the aggregation and prion propensities of the K18-domain.