The rise and rise of proteostasis

Proteostasis, the myriad mechanisms that ensure our proteins work correctly, is key to healthy ageing. We speak to Dr Della David and Dr Rahul Samant about their cutting-edge research, why proteostasis is such a growing area of strength at the Institute, and how the new UK Proteostasis Network will help accelerate research in the field.

In understanding health and disease, it’s impossible to overstate the importance of proteins. The smooth working of a plethora of proteins—the so-called proteome—ensures that our cells function correctly and can adapt to a changing environment. That’s why proteostasis—the quality control mechanisms that keep proteins working properly—is a burgeoning field of research.

Many diseases—particularly those of ageing—stem from problems in proteostasis and the breakdown of proteostasis is recognised as a hallmark of ageing itself. Dr Della David, one of several group leaders at the Institute who focuses on proteostasis, uses the tiny nematode Caenorhabditis elegans to discover mechanisms to help combat age-related diseases and promote healthy ageing.

“Keeping the integrity of your proteome is really challenging but so important for life; every organism needs these mechanisms that protect the proteome. These mechanisms look after the proteins, make sure they function at the correct location, and ensure their disposal when they become damaged or aggregate, so proteostasis is absolutely fundamental and poor proteostasis accelerates the ageing process,” she explains.

Dr Rahul Samant, also a group leader in the Signalling programme, works on cellular senescence, another hallmark of ageing. As we age, accumulation of damage—including through proteostasis faults—causes a build up of large cells that have lost their intended function in our tissues. No longer able to divide or regenerate but persistent and hard to kill, these so-called zombie cells accumulate in ageing tissues causing chronic inflammation.

“Fifteen years ago it was unclear whether these cells were a cause of ageing or just correlated with it. Then, researchers genetically engineered a mouse with no zombie cells and found they not only lived longer but were healthier,” he says. The same has since been found in other species and researchers are working to unravel the fundamental biology to explain why.

Using a range of different human cell types, Samant is looking at how the same senescence stress drives diverse responses in proteostasis.  “At first, our question was highly focused: if you introduce this stress, what happens to the molecular circuitry? In fact, there are diverse responses, so we are looking at whether there is more commonality in all types of senescent cells in our body rather than in senescent and non-senescent cells of the same type.”

This understanding will be crucial to drug discovery, he says. “We always look for magic bullets – drugs that will kill every senescent cell in the body. Some think we’ll be able to find this if we look harder. Others think there is no unifying factor and that multiple treatment options will be needed depending on the exact type of senescence driving that disease.”

Answering such challenging questions demands different perspectives and solid technical capabilities, he says. “Diversity is important for understanding ageing and proteostasis better, that’s one of the Institute’s great strengths. I don’t know anywhere else working on proteostasis across such a diverse set of organisms, including yeast, worms, flies, mice and human cells. The other key strength is the breadth of our expertise, both scientifically in our research groups, but also of the technical staff in our facilities.”

“For example, we work really closely with the mass spectrometry facility at the Institute. For us, the facility is not simply a service, they are partners we actively collaborate with. The same is true with bioinformatics. It’s an iterative process built on two-way communication. It's one of the main reasons I joined the Institute,” explains Samant.

Another example of the Institute’s leadership role and collaborative ethos is the UK Proteostasis Network, established in 2024 with David and colleague Dr Oliver Florey as two of its cofounders. “The aim is to bring the UK proteostasis community together, hold events and empower early career researchers because although the UK has great strengths in proteostasis research, we could achieve even more by sharing ideas and expertise,” David explains.

During its first 12 months, the Network has gone from strength to strength. Its first two-day meeting in Spring 2024 attracted 170 attendees from academia and industry and a second will follow in 2025 — evidence of the community’s huge enthusiasm to work together and build the Network.

“Individual groups are doing amazing work and I’m super excited about animal and plant scientists working together to cross pollinate ideas,” she concludes. “And now is absolutely the right time. We have a clear view of what we need to discover. We are at a critical moment to bring the community together and realise its potential.”