PhD thesis finds protein domain BRICHOS capable of combatting harmful protein aggregates created in the body

Various aggregates of misfolded proteins may accumulate in our bodies and therefore cause many diseases. One such disease is Alzheimer's disease, which is currently untreatable and is characterised by the toxic aggregation and final accumulation of Amyloid-β (Aβ) peptide as amyloid plaques in human brain tissue. Fortunately, the body has its own protective mechanisms in the form of chaperones, which fight the formation of unfavourable and harmful protein aggregates. Molecular chaperones play an important role in ensuring the homeostasis of proteins – they help target proteins achieve their characteristic functional structure, assist proteins in transportation, stop them from forming aggregates and participate in the removal and degradation of misfolded proteins.

In the course of this thesis, research was mainly done on the BRICHOS domain (more specifically the proSP-C, Bri2 and Bri3 BRICHOS domains), but also on less researched peptide Thioredoxin 80 (Trx80)   - their role in the aggregation of other proteins and their activity as molecular chaperones was assessed. BRICHOS is a protein domain consisting of approximately 100 amino acid residues and was initially characterised in the proteins such as Bri2, Chondromodulin-1 and surfactant protein C (proSP-C). Those names also gave the domain its name.

Past research has shown that the recombinant Bri2 BRICHOS peptide can also block Aβ fibrillation in vitro (in so-called laboratory conditions in a test tube) and do so more effectively than has been observed with proSP-C BRICHOS. However, the in vivo function, i.e. the way the Bri2 BRICHOS domain functions in the body, has not been as closely researched. The more specific aim of this thesis was to determine how said chaperones influence the Aβ fibrillar and so-called amorphous aggregation common for other proteins in general.  In addition, there was a desire to learn whether by using these chaperones, it was possible to avoid the toxicity caused by protein misfolding – here, the focus was on the Aβ42 peptide. 
In this thesis, a fruit fly (in Latin Drosophila Melongaster) was used to look into the effect chaperone domain BRICHOS and Trx80 have on the Aβ induced toxicity. “I found that the overexpression of the BRICHOS domain as well as Trx80 in the fruit fly reduces the deposition of Aβ42 and considerably improves changes caused by the toxicity of Aβ42,” explained Poska. “In both cases, we observed improved life expectancy and increased efficiency in climbing tests for the flies. In addition, to our great surprise, compared to other peptides that have been researched (Trx80 and proSP-C), Bri2 BRICHOS was found to create an accumulation of Aβ42 in the neurons of the mushroom body of the fly's brain (an area in insect brains associated with the sense of smell, memory and learning ability). This was a clear indication of the fact that all BRICHOS domains (though they have a similar structure) are not equal as chaperones and may work in different ways in the body.” 

One of the most important discoveries in the dissertation might be that the influence of the BRICHOS domain is much more extensive than previously thought. It was found that Bri2 and Bri3 BRICHOS, but not proSP-C BRICHOS, also bind to denatured amorphously aggregating protein intermediates and therefore avoid final their aggregation. As a side note, it may be added that the BRICHOS domain of Bri3  had not been studied this extensively before. The observation above means that some BRICHOS domains are potentially more comprehensive chaperones and capable of halting the aggregation and accumulation of amyloid-like as well as amorphously aggregating proteins. Therefore, an attempt was made to explain where the functional differences of the BRICHOS domains come from.

Finding new chaperones and researching their mechanisms is important. Increasing the efficiency of the defence mechanisms present in the body could potentially be one way to influence the course of diseases caused by the aggregation of various proteins. Chaperones could also be potential drug candidates for diseases that do not yet have a treatment.

On 2 February 2021 at 11:00, Helen Poska, a PhD student at Tallinn University's School of Natural Sciences and Health, will defend their PhD thesis “In vitro and in vivo studies of molecular chaperone activity against fibrillar and non-fibrillar protein aggregation”.

The public defence will take place in auditorium M648 at Tallinn University.
The public can view the defence and ask the degree candidate questions on Zoom. 

The dissertation supervisors are Professor Jan Johansson and researcher Jenny Presto from the Karolinska Institute. The opponents are senior lecturer Sofie Nyström from the University of Linköping and Professor Peep Palumaa from Tallinn University of Technology.

The dissertation is available in the ETERA digital environment of TU Academic Library.