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March 11, 2019

Pregnancy discovery unlocks clue to Alzheimer’s, arthritis and other ageing diseases

Special protein helps protect women during pregnancy

A discovery about how the bodies of pregnant women cope with biological stresses that promote protein damage could unlock new ways to treat or even prevent age-related disorders, from Alzheimer’s and arthritis to macular degeneration and heart disease.

An international research team found that a powerful protein from the blood of pregnant woman, known as pregnancy zone protein (PZP), inhibits the aggregation of misfolded proteins, including those associated with preeclampsia and Alzheimer’s disease.

Their discovery is published in high-profile journal Proceedings of the National Academy of Sciences USA (PNAS).

Proteins can be considered the molecular machinery of the body, performing diverse functions that are necessary for life. During pregnancy a woman’s body undergoes dramatic changes. Some of these changes are known to increase levels of protein damage (also known as misfolding).

During pregnancies, protein misfolding is associated with preeclampsia. Women with preeclampsia develop high blood pressure, raised protein in their urine and other conditions which can increase risks at childbirth.

Protein misfolding also underlies a large number of age-related disorders, including Alzheimer’s and arthritis.

¾«¶«´«Ã½ of ¾«¶«´«Ã½ and PhD student Jordan Cater was lead author of the research paper.

“We have known for a long time that it is bad for the body to accumulate damaged proteins. Therefore we predicted that in healthy pregnancy, mothers somehow adapt to cope with protein damage in a unique way,” Mr Cater said.

“Our investigation revealed that PZP can bind to and stabilise misfolded proteins and subsequently prevent their aggregation. We were surprised by how potent the activity of PZP is in this regard when compared to other similar proteins. These are very exciting findings.”

Both of Mr Cater’s supervisors, UOW molecular biologist Professor and Flinders ¾«¶«´«Ã½ medical biochemistry researcher Dr Amy Wyatt, were co-authors of the paper.

“This is the first evidence of a major maternal adaptation that allows mothers to withstand elevated levels of protein misfolding in pregnancy. Failure of this system potentially triggers the accumulation of misfolded proteins in preeclampisa, and could also have relevance to some age-related protein misfolding disorders,” Dr Wyatt said.

Better understanding of how mothers normally deal with protein misfolding in pregnancy is an exciting new frontier that has the potential to inform the development of new therapies and diagnostic strategies for some of the most common and debilitating disorders of ageing – as well as for preeclampsia.

“Our future work will focus on further characterisation of the activities of PZP, including investigation of the potentially protective role of PZP in human diseases including preeclampsia and Alzheimer’s disease,” Mr Cater said.

The research team also included prominent international experts Professor Irina Buhimschi (¾«¶«´«Ã½ of Illinois) who originally identified Alzheimer’s-like plaques in the placenta in preeclampsia patients, and Professor Christopher Dobson (¾«¶«´«Ã½ of Cambridge, UK), a world leader in the study of protein misfolding.

The paper was edited by Professor Ulrich Hartl, director of the Max Plank Institute of Biochemistry in Germany, who was an early pioneer in the study of molecular chaperones – the biological machinery responsible for controlling protein folding.

ABOUT THE PAPER

‘Human pregnancy zone protein stabilises misfolded proteins including preeclampsia- and Alzheimer’s-associated amyloid beta peptide’, by Jordan H. Cater, Janet R. Kumita, Rafaa Zeineddine Abdallah, Guomao Zhao, Ana Bernardo-Gancedo, Amanda Henry, Wendy Winata, Mengna Chi, Brin S. F. Grenyer, Michelle L. Townsend, Marie Ranson, Catalin S. Buhimschi, D. Stephen Charnock-Jones, Christopher M. Dobson, Mark R. Wilson, Irina A. Buhimschi and Amy R. Wyatt is published in the Proceedings of the National Academy of Sciences USA (PNAS).

The research was supported by funding from the National Health and Medical Research Council, an Australian Institute of Nuclear Science and Engineering (AINSE) postdoctoral award and a Research Training Program Scholarship (Commonwealth Government of Australia). Additional funds were from the ¾«¶«´«Ã½ of ¾«¶«´«Ã½ and Illawarra Health and Medical Research Institute.