Discovery in songbird brings new insights into cholesterol transport and viral entry

Claudio Mello, M.D., Ph.D., professor of behavioral neuroscience in the School of Medicine at Oregon Health & Science University

New research reveals an evolutionary genetic difference that sets songbirds up to have high cholesterol. The birds, though, thwart expectations.

A study published today in the journal Proceedings of the National Academy of Sciences reveals that zebra finches and other songbirds have a low-density lipoprotein receptor (LDLR) gene surprisingly different than other vertebrates. These findings contradict a widely held belief that LDLR structure and biological function is largely conserved across vertebrates.

The function of LDLR, which is responsible for cellular uptake of LDL-bound cholesterol, or “bad cholesterol,” has been thought to be conserved across vertebrates. A team of OHSU-led scientists found that in the case of songbirds, key domains for the function of the receptor were lacking. Mutations like this are a genetic cause of severe high cholesterol and high risk for cardiovascular disease in mammals. Surprisingly, this evolutionary loss has not resulted in high cholesterol for songbirds; they carry most of their cholesterol in high-density lipoprotein, HDL, or “good cholesterol.”

“These songbirds seem to have adapted to the LDLR changes and have developed a healthy cholesterol profile, or ratio of low to high cholesterol,” said senior author Claudio Mello, M.D., Ph.D., professor of behavioral neuroscience in the School of Medicine at Oregon Health & Science University. “It suggests that songbirds may have some sort of protection from cardiovascular disease.”

LDLR and viral infectivity

These findings provide insights into the genetics and evolution of viral infectivity and cholesterol transport mechanisms in vertebrates.

The discovery was made in the zebra finch and then confirmed in all five songbird species examined, but not in non-songbird avian groups. Further research into these songbirds could bring new knowledge into lipid production, transport and clearance mechanisms. This unsuspected evolutionary loss also has implications for viral entry, cellular transport systems and, potentially, gene therapies.

LDLR is also the main receptor for the G protein of vesicular stomatitis virus (VSV G) and are used to pseudotype, by coating, lentiviral vectors for gene manipulation in animals and gene therapy trials in humans. The lack of key functional domains in LDLR explains the low susceptibility of finches to lentiviruses, a family that includes HIV, pseudotyped with VSV-G. Besides the implications for improving gene manipulation tools in finches, this study illustrates the fascinating co-evolution and interplay between viral entry and basic cellular transport systems.

The genetic discovery is part of a broader initiative to generate high quality genome sequences in a large number of animals. It was also part of a three-year initiative funded by the National Science Foundation enabling researchers at OHSU and other institutions to study the genetic makeup of zebra finches, an important model in neurobiology.

Co-authors include Sergio Fazio, M.D., Ph.D.; Joshua Miles, Paul Mueller, Ph.D., and Hagai Tavori, Ph.D., Knight Cardiovascular Institute, OHSU; Peter V. Lovell, Ph.D., Samantha R. Friedrich and Christopher R. Olson, Department of Behavioral Neuroscience, OHSU; and Tarciso Velho, Ph.D., and Carlos Lois, Ph.D., California Institute of Technology.

The research was supported by funding from the Instituto Serrapilheira grant award 1709-17844; National Institutes of Health award R21OD028874; and National Science Foundation award 1645199.


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