The impact of the chromatin environment on protein aggregation
Cell Biology
Final Report Abstract
Increased life expectancy comes along with a higher prevalence of devasting neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), Alzheimer’s and Huntington’s diseases. All these diseases are incurable to date and have in common that for each disease specific proteins misfold and aggregate in the brain. It is thus crucial to improve our knowledge about the process of protein misfolding and aggregation and how it is influenced. Since protein aggregates are toxic for the cell, we need to find ways to prevent these aggregation-prone proteins from aggregating not only for the ultimate goal of a possible therapeutic treatment but initially also to find a way to be able to study these proteins in a non-toxic way. A very efficient way to control protein states and precisely coordinate the transition from a liquid to solid state, the latter one resembling the aggregated state, is performed by spiders during the spinning of spider silk. The state is tightly regulated by the N- terminal domain (NT) of spider silk proteins in combination with changes in the pH. A modified version of the NT-tag, the NT*-tag, was shown before to keep e.g. recombinant amyloid β, the peptide that is found aggregated in Alzheimer’s disease, soluble. The results gained in this project show that these observations are transferrable to the intracellular environment. Upon stably introducing a construct that highly aggregates in a regulatable fashion into human cells, we showed that aggregation is prevented if the NT*-tag is introduced into different positions of the construct. This allowed us to target the inducible, aggregation-prone construct to different subcellular sites which will help to understand the impacts of different localizations on aggregate formation and the aggregates per se. This is important since it is known that aggregates form at different subcellular sites depending on the neurodegenerative disease. In the case of Huntington’s disease aggregates are found in the nucleus and the cytosol and the subcellular localization has been suggested to influence the toxicity of the aggregated proteins. Further characterization is ongoing but our preliminary data already show that the spider NT*-tag has high potential to be used in order to better understand the process of protein aggregate formation, the native function of the disease-causing proteins and, on the longer perspective, to explore the therapic potential of anti-aggregation domains.
Publications
- (2020), Functionalization of amyloid fibrils via the Bri2 BRICHOS domain. Scientific Reports
Biverstål H., Kumar R., Schellhaus A.K., Sarr M., Dantuma N.P., Abelein A., Johansson J.
(See online at https://doi.org/10.1038/s41598-020-78732-1)
