The impact of the chromatin environment on protein aggregation

• Applicant: Dr. Anna Katharina Schellhaus
• Subject Area: Biochemistry ; Cell Biology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 402702701

Proteins fold into specific conformations. If this is impaired, unfolded or misfolded proteins form toxic aggregates that can cause age-related neurodegenerative diseases like Amyotrophic lateral sclerosis (ALS) or Alzheimer’s disease. Protein aggregates are further sequestered into bigger and less-dynamic inclusion bodies. If these are even more toxic or serve a protective role by reacting less dynamic with the environment is still controversial. Aggregation-prone proteins usually contain unstructured domains which can also induce phase separation. A process that allows two liquids to co-exist without major mixing, as we also observe in a unmixed vinaigrette showing a vinegar and oil phase, and recently emerged as concept of cellular organization. Especially proteins with unstructured, low sequence complexity, meaning only a subset of the proteinogenic amino acids are used or multivalent domains, interacting with several interaction partners simultaneously are capable of inducing phase separation. The concentrations of macromolecules is increased in the separated liquid phase and thus can stimulate protein aggregation. Indeed, for some proteins found misfolded in neurodegenerative diseases it was already shown that they induce phase separation, especially in the mutated, pathogenic version. Also in the nucleus different structures were shown to form via phase separation, e.g. the nucleoli and even heterochromatin, the densely-packed, transcriptionally inactive chromatin. Many of the proteins found to be mutated and misfolded in neurodegenerative diseases have functions in transcription and chromatin remodeling. The aim of my project is to investigate the influence of the chromatin environment on intranuclear protein aggregation. The chromatin and the nucleoplasm are an environment with high macromolecular density. It is conceivable that phase separation and protein aggregation is directly influenced by the surrounding chromatin, respectively. By targeting aggregation-prone proteins to different, specific chromatin sites, I will analyze if the proximity to chromatin or other nuclear structures like the nuclear envelope are influencing the folding and aggregation behavior of the proteins and formation of inclusion bodies. Furthermore, I also want to study the impact of these inclusions on the chromatin structure and transcriptional activity. The project will shed light on the impact of chromatin on the development of neurodegenerative diseases and which role phase separation plays in this context, respectively.

• DFG Programme: Research Fellowships
• International Connection: Sweden
• Host: Professor Dr. Nico P. Dantuma