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Rare disease cell research finds new link to inflammation

“How many people actually have this disease?”

This is a potentially triggering question at a family barbecue. I had just finished explaining why I had recently traveled to the United States to work on samples from patients with a rare disease called Proteasome-related autoinflammatory syndrome (PRAAS). None of my family had ever heard of this disease, which is not surprising. There are less than a thousand patients diagnosed with PRAAS worldwide. So why work there?

Rare disease research is interesting not only because of the people it helps, but because of what it can teach us about more common diseases. Photo: Getty Images

Why not rather work on a neurodegenerative disease like Parkinson’s disease for which there are more 2,225 new cases diagnosed each year in Australia alone? Or maybe a chronic viral infection? In 2019 more 150,000 people in Australia were living with chronic hepatitis B virus infection.

This is a good point and arguments can be made to prioritize investments where the most good can be done. But it is clear that we cannot abandon people and families with rare diseases either.

It is therefore encouraging that in 2020 Australia has launched its National strategic action plan for rare diseaseswhich consists of dedicating funds from the Fund for the future of medical research and the National Council for Health and Medical Research.

But also, it must be remembered that research into rare diseases brings new knowledge and new understanding not only for the potential benefit of the patients concerned, but also for our fundamental understanding of how the body works and fights diseases in general.

Take for example PRAAS. The clinical presentation of PRAAS involves repetitive fever, severe skin rashes, immobility in the joints, muscle wasting, and delayed physical development. Until 2018, the prognosis of PRAAS was dire. While immunosuppressive drugs could alleviate some symptoms, patients eventually succumbed to respiratory or heart failure. But, in 2018, a new treatment was designed to stop the spread of inflammation, and patient outcomes have improved.

Like most rare diseases, it is caused by inborn genetic errors – in PRAAS these errors affect a cellular component called the proteasome. Proteasomes are complexes in our cells that identify and destroy unwanted proteins that might otherwise accumulate and eventually kill the cell.

Computer illustration of the proteasome (right) destroying tumor proteins (left) that have been tagged to be destroyed by regulatory proteins (yellow). Photo: Getty Images

The problem in PRAAS patients is that genetic errors occur in the creation of proteasome complexes, which means that the proteasome is not assembled correctly and cannot function.

As a result, dangerous levels of protein ‘waste’ accumulate in the cells of these patients. Interestingly, this induces an inflammatory response from the cell that resembles the inflammatory response of cells to a viral infection.

Now that’s very interesting, because in diseases like Parkinson’s disease, unwanted proteins have long been observed to build up in patients’ cells, and it’s increasingly understood that inflammation contributes to Parkinson’s disease. Additionally, viruses like hepatitis B have evolved mechanisms to clog the proteasome of our cells so that they can replicate inside us.

These observations and many others demonstrate that the accumulation of unwanted proteins can trigger an inflammatory response from a cell, however, the specific molecular mechanism of how this occurs was not known, until we let’s look at PRAAS.

Studying how loss of function in the proteasome drives inflammation in something like Parkinson’s disease or a chronic viral infection is incredibly difficult because the cause and action of these diseases are complex, involving genetic and environmental factors.

In contrast, PRAAS has a defined genetic mutation that results in the specific loss of proteasome function, which directly leads to inflammation. These are dots that we can connect.

Super resolution microscopy images of a healthy cell (left) and a cell genetically modified to model PRAAS (right) with the nucleus in blue. In the healthy cell, there is only a small amount of IL-24 (red) inside the cell, but in the PRAAS cell, IL-24 accumulates in the cell, which which leads to inflammatory disease in PRAAS. Image: Provided

By using PRAAS as a system to study how our cells perceive the accumulation of protein waste, our research The team discovered that a pattern recognition receptor called protein kinase R (PKR) recognizes the buildup of a certain unwanted protein called IL-24.

Now, IL-24 functions normally outside the cell, so it can only accumulate inside the cell when the proteasome isn’t there to clear it. If IL-24 is not eliminated by the proteasome, it is detected by the PKR which then triggers an inflammatory response.

Curiously, PKR is different from many other pattern recognition receptors. In addition to causing inflammation, it also activates a secondary pathway to inhibit the cell’s generation of new proteins. When a cell is stressed, the generation of new proteins can increase the accumulation of protein waste.

The action of PKR is therefore twofold: it causes inflammation to alert cells in the surrounding environment to a possible infection and it also tries to reduce the load of protein waste on the proteasome, hoping that the cell will return to normal.

Inflammation is important for clearing viral infections, so activating this pathway can protect cells from infection. However, when a cell cannot return to normal due to inborn genetic errors in a disease like PRAAS, activation of PKR can lead to chronic inflammatory disease.

By studying PRAAS, we were able to find a previously unknown link between inflammation and the accumulation of unwanted proteins. This identified PKR as a potential target for new therapies aimed at inhibiting chronic inflammation in PRAAS.

Dangerous rare diseases acquired at birth mean that patients are usually children. Photo: Getty Images

Although discovered in a rare disease, this pathway may have implications in neurodegenerative diseases such as Parkinson’s where protein accumulation, inflammation and PKR activation have all been observed but not yet functionally associated.

Additionally, this may have implications for fighting viral infections since it is possible that this particular inflammatory pathway has evolved to fight viral infection.

Understanding this pathway and gaining this information was only possible because PRAAS has a known genetic cause.

In Australia, a disease is considered rare if it affects fewer than five in 10,000 people. means collectively, approximately 8 percent of Australians, or two million people, live with a rare disease.

Unfortunately, diseases like PRAAS are life-threatening or chronically debilitating, and since they are usually caused by inborn genetic errors, the majority of patients are children.

These two million Australians living with a rare chronic disease are actually helping us to deepen our understanding of human physiology and accelerate the development of treatments for thousands of common and rare diseases and conditions. Their diseases deserve to be studied.

February 28 is Rare sick dayawareness and change for the 300 million people worldwide living with a rare disease, their families and caregivers.

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