Gravitation award for FLOW: "We will be able to steer the fates of proteins"

The Dutch government is investing 23 million euros in a major research project led by Utrecht University. The consortium of researchers involved in FLOW will, for the first time, comprehensively chart the supervision of specific proteins within the cell, from cradle to grave. Ultimately, leveraging this understanding, they aim to exert control over the fate of these proteins. Such insights could pave the way for novel therapeutic approaches targeting diseases like Parkinson's and cystic fibrosis.

The funding is part of the esteemed NWO Gravitation Programme, a government initiative that, for a decade already, has been dedicated to supporting top-tier research. Biennially, teams of researchers affiliated with Dutch universities can secure funding. Initially, research projects receive half of the allocated funds, with the remainder granted upon successful evaluation after five years. The principal investigators are Ineke Braakman (Utrecht University), Mireille Claessens (Twente University), Friedrich Förster (Utrecht University), Mark Hipp (UMC Groningen), Stefan Rüdiger (Utrecht University) and Alfred Vertegaal (Leiden UMC).

Unreal

Professor Ineke Braakman had to wait a long time for the results, which meant that the project had already faded somewhat into the background. The surprise hence was all the more profound when she, as the project's leader, received the relieving phone call. "It felt completely surreal," she recalls, "but in the evening it slowly sank in.” It brings both joy and the realisation that lots of activities suddenly need to be set in motion. “The top priority now is to convene the consortium and embark on the tasks at hand."

Our aim is to make a substantial impact by examining the same two proteins across diverse scientific domains

Combining disciplines

For the very first time, researchers are set to construct a comprehensive overview of all the mechanisms contributing to the functionality of specific proteins within the cell. Their objective is to unravel precisely how the cell ensures accurate folding and maintenance of proteins, spanning from their creation through their functioning to eventual degradation. Additionally, they want to know how the cell disposes of a protein if it folds incorrectly.

Achieving this entails deciphering a network of helper proteins, commonly referred to as chaperones. Over the past fifty years, science has been studying this issue, albeit with a focus on various proteins and facets of the process. "Our aim is to make a substantial impact by examining the same two proteins across diverse scientific domains," Braakman elucidated. "In doing so, we aim to achieve a complete understanding of the entire system."

Protein diseases

Gaining a comprehensive understanding of the processes underlying protein function is crucial. This is because failures in these processes often lead to protein-related diseases. In Loss-of-Function (LoF) diseases, like metabolic disorders and cystic fibrosis, the malfunctioning arises from a specific protein's failure to adopt the correct structure. Conversely, Gain-of-Toxicity (GoT) diseases such as Alzheimer's and Parkinson's result from proteins improperly folding, forming toxic aggregates.

Within this research project, scientists are focusing on two proteins: CFTR, implicated in cystic fibrosis when dysfunctional, and alpha-synuclein, associated with Parkinson's disease when malfunctioning.

Novel therapies

In the second branch of the research, scientists aim to replicate the chaperone networks and processes responsible for protein care in a controlled laboratory setting. "The goal is ambitious”, Braakman remarked, "but as chemists often assert: true comprehension is only acquired when you can build it." This knowledge should eventually empower researchers to manipulate the system directly. "This way, we'll soon have the ability to influence the destiny of these proteins," Braakman added. Such capabilities will serve as the groundwork for novel therapies targeting protein-related ailments like Parkinson's and cystic fibrosis. Additionally, the results will make it easier to control a wide range of other disease-related proteins for medical and biotechnological purposes.