Could a pregnancy protein hold promise for new drugs?
Australian scientists have identified a remarkable adaptation of pregnancy in which pregnancy zone protein can stabilise the misfolding of proteins, a cause of a range of age-related and other serious diseases. Could PZP’s newly found mechanism of action represent a new therapeutic approach for these disorders? Allie Nawrat reports.
Researchers at Flinders University, Australia, have discovered the mechanism through which pregnant women’s bodies deal with biological stresses and associated protein misfolding.
The team, led by Dr Amy Wyatt, noted higher levels of a protein called pregnancy zone protein (PZP) in pregnant women and found that this protein stabilises misfolded proteins and maintains protein homeostasis.
Better understanding of PZP’s mechanism action is essential because it could open up novel areas of research for treatments for age-related diseases and other serious indications lacking adequate therapeutic options.
According to Wyatt, who is a senior lecturer in medical biochemistry and head of the protein misfolding and inflammation laboratory at Flinders University, “protein misfolding is implicated in over 40 human diseases including Alzheimer’s disease, arthritis, macular degeneration, heart disease and preeclampsia.”
Understanding PZP’s mechanism of action
The researchers started investigating PZP after “studying a closely related protein – alpha-2-macroglobulin - that is not pregnancy-associated, but constitutively abundant in human blood” and its role in stabilising misfolded proteins.
Using “generous donations of blood plasma from hundreds of women in the UK and Australia”, as well as “placentas donated by women in the USA”, Wyatt and her team found that “PZP stabilises a broad range of misfolded proteins, including disease relevant substrates and commonly used model proteins.”
PZP will stabilise any protein provided that its misfolding induces the exposure of normally buried hydrophobic surfaces.
Wyatt believes, “PZP will stabilise any protein provided that its misfolding induces the exposure of normally buried hydrophobic surfaces.”
She says the study’s findings are particularly exciting as it, “is the first evidence that in pregnancy, major maternal adaptations enhance the ability of the body to cope with elevated protein misfolding.”
Clinical applications of PZP findings
Elevated PZP levels experienced in pregnant women are also found to a lesser extent in “a large number of inflammatory states including Alzheimer’s disease, viral infection, Behcets syndrome, inflammatory bowel disease and arthritis.”
“This may be a normal response to enhance the body’s ability to deal with protein misfolding in response to physiological stresses associated with inflammation,” according to Wyatt.
Therefore, she concludes, greater understanding of the role of PZP can help researchers “to design new strategies to combat protein misfolding in disease.”
This is important because many of these conditions represent an unmet clinical need. The cause of Alzheimer’s disease, in particular, is largely unknown so there remains disagreement within the medical community about the cause of the condition and, therefore, how best to treat it.
Greater understanding of the role of PZP can help researchers to design new strategies.
However, as Wyatt explains, PZP inhibits the aggregation of misfolded proteins, such as amyloid beta peptide, which is the centre of one of the core Alzheimer’s hypotheses.
There is a similar lack of clarity about the cause of inflammatory bowel disease, which encompasses a range of inflammatory conditions of the colon and small intestine.
Next stages of research into potential of PZP
As a result of their findings, the Flinders researchers are using their newfound knowledge about PZP’s so-called ‘chaperone’ properties to develop “strategies to make constitutively abundant alpha-2-macroglobulin function in a more PZP-like manner.”
This is the first step towards translating the research into developing new drugs for misfolding protein-based diseases, but the team does not currently have any relationships with the pharma industry to help them to achieve this.
This is the first step towards translating the research into developing new drugs.
Wyatt’s researchers are also seeking to understand “how the body disposes of the stabilised PZP-misfolded protein complex” and “to determine low levels of PZP are directly responsible for the accumulation of misfolded proteins in preeclampsia.” Similar plaques to those formed in Alzheimer’s patient’s brains are found in preeclampsia.
Preeclampsia is a serious condition that occurs during pregnancy, which is characterised by high blood pressure and high protein levels in urine. It affects approximately 6% of pregnancies globally and currently the only treatment is to deliver the baby.
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