19B. Aging-related transcription stress in chemotherapy-induced Dementia’s

Besides the causal amyloid plaques and tau tangles, a main and frequently forgotten hallmarks of dementia is ageing, which itself is predominantly driven by stochastic accumulation of DNA damage. Similarly, childhood cancer survivors are often confronted early in life with ageing-related neurocognitive deficits, including dementia, as consequence of long-term side-effects of the DNA-damaging treatment they received.

Persistent DNA lesions (as introduced by anti-cancer therapies) may interfere with transcription, thereby triggering transcription stress. Consequently, cellular transcriptional profiles change and the expression of particularly larger genes, including various synaptic genes, declines, negatively affecting neuronal functioning. Furthermore, the transcription stress-induced disbalanced gene expression is suggested to lead to imbalanced polypeptide production and consequent proteotoxic stress, a common age-related phenomenon. This may eventually overload the cellular proteostasis capacities, resulting in the increased abundance and sequestration of misfolded proteins into (neurotoxic) inclusions, and subsequent neurodegeneration, cognitive decline, and premature segmental (brain) ageing; all contributing to dementia pathology. Currently, the impact of ageing-related transcription stress for dementia onset and pathology remains enigmatic.

This project aims to identify the impact of chemotherapy-induce DNA damage and age-related transcriptional stress on dementia onset and pathogenesis. In addition to a correlative study assessing the level of transcription stress in various dementia cohorts, we aim to gain mechanistic understanding into the preservation as well as consequences of transcription stress for the various cell-types of the brain, using human iPSC-derived cellular model systems. We anticipate that this work will disclose the importance of chemotherapy-induced and ageing-related transcription stress for dementia onset and pathology, and reveal critical cell type-specific protein quality control determinants functionally affected by stochastic DNA damage accumulation with age. Overall, our findings may open new avenues for the design of new therapeutic strategies to combat chemotherapy-induced dementia and other forms of neurodegeneration by modulation of transcription- and eventually proteotoxic-stress.

Necessary skills for this position:

• Master’s degree in Neuroscience, Life Sciences, Biomedical Sciences or a related field.
• Hands–on experience in cellular and molecular technologies, including cell culture, confocal microscopy, flow cytometry, cloning and gel electrophoresis, are preferential.
• Background in Neuroscience or Biomedical Informatics are considered an advantage.