Box 1. Once more into the misfoldome.

In addition to identifying a method for diagnosing preeclampsia, the report in Science Translational Medicine suggests that the etiology of the disease involves the misfolding of multiple proteins-a finding the team thinks could eventually lead to a therapy.1

The team showed that urine from women with preeclampsia contained amyloids from at least six different proteins that were not found in urine from women with uneventful pregnancies: albumin and a1-antitrypsin (AAT; A1AT; SERPINA1), which the team had previously identified;2 amyloid precursor protein (APP); ceruloplasmin ferroxidase (CP); interferon-a inducible protein 6 (IFI6); and immunoglobulin-k light chains.

However, "not all of the preeclampsia patients had all of the proteins in their urine," said team leader Irina Buhimschi, who is a professor of pediatrics and obstetrics/gynecology at The Ohio State University College of Medicine and director of the Center for Perinatal Research at Nationwide Children's Hospital.

Moreover, the team tested patient urine with conformation-specific antibodies against each amyloid and found variations in amyloid types and toxicities among the patients with preeclampsia. For example, she said, "we saw that women with milder cases of preeclampsia had aggregates that were less toxic."

The heterogeneity of the urine amyloids might account for differences in clinical presentation among the subtypes of preeclampsia-including mild, severe, early onset, and atypical, Buhimschi said.

She also said that toxic amyloids that affect specific tissues may explain the association of preeclampsia with other gestational conditions such as hemolysis, liver enzymes and low platelets syndrome, which is sometimes considered part of the preeclampsia spectrum, and peripartum cardiomyopathy, for which preeclampsia is a risk factor.

Thus, the team's long-term goal is to translate its findings about amyloid compositions and conformations into a therapy for preeclampsia.

"This could be done in two ways-by inhibiting protein misfolding in general or by inhibiting more specific aggregates and their toxic effects" with conformation-specific antibodies, she said. "The immune activity of the antibodies could also guide vaccine development."

She added, "We think there are more than just the six types of proteins described in our current paper-this was just the tip of the iceberg. We have now compiled a complete catalog of the proteins and fragments found in preeclampsia urine."

Matthew Cooper, founder and CEO of Carmenta Bioscience Inc., said that such a catalog of proteins and their associations with differing subtypes of preeclampsia could help stratify patients. But he cautioned that it is not yet clear whether the misfolded proteins identified by the team were a cause or an effect of the disease.

Nevertheless, "I would love to see therapeutic targets come of this work," he said. "I truly think the preeclampsia research community is on the cusp of understanding the disease process in a way that will yield therapeutic targets."          -MJH