Researchers trace rare hereditary diseases

Malfunctions of the FLVCR1 and FLVCR2 proteins are known to lead to rare inherited diseases in humans that cause motor, sensory and neurological disorders. However, the biochemical mechanisms behind this and the physiological functions of FLVCR proteins have been unclear to date. An interdisciplinary team of researchers from Frankfurt am Main, Singapore and the USA has now deciphered the 3D structures of FLVCR proteins and their cellular functions. Researchers have shown that proteins transport the cellular building blocks, choline and ethanolamine. Their findings contribute significantly to the understanding of the pathogenesis of rare diseases and the development of new therapies.

In hospital TV series like Scrubs or Dr. House, doctors seek accurate diagnoses and possible treatments for patients with sometimes strange or strange symptoms. In reality, this process often takes years for those affected by rare diseases. In many cases, there is no effective treatment and therapeutic options are limited.

Approximately 6-8% of the world’s population suffers from a rare disease. That’s about 500 million people, even though each of the more than 7,000 different diseases affects only one in 2,000 people. Because these diseases are so rare, medical and scientific knowledge about them is limited. There are only a few experts worldwide and social awareness is lacking.

Unraveling protein structure and function to understand disease and develop therapies

An international team of researchers led by Schara Safarian, project group leader at the Max Planck Institute for Biophysics, as well as independent group leader at the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and the Institute of Clinical Pharmacology at Goethe University Frankfurt, has now investigated the structure and cellular function of two proteins, FLVCR1 and FLVCR2, which play a causal role in a number of rare hereditary diseases. Scientists have published their findings in the prestigious journal Nature.

Dysfunctions of FLVCR1 and FLVCR2 due to gene mutations cause rare diseases, some of which result in severe visual, motor and sensory disorders – such as posterior column ataxia with retinitis pigmentosa, Fowler’s syndrome or neuropathies sensory and autonomous. The latter, for example, can lead to a complete loss of pain sensation. “In many diseases, including rare ones, the cellular structures in our body change and this leads to malfunctions in biochemical processes,” says Schara Safarian. “To understand the development of such diseases and to develop therapies, we need to know how these proteins are structured at the molecular level and what functions they perform in healthy cells.”

FLVCR1 and FLVCR2 transport the cellular building blocks choline and ethanolamine

Scientists have discovered that FLVCR 1 and FLVCR2 transport the molecules choline and ethanolamine across our cell membranes. “Choline and ethanolamine are essential for important bodily functions. They support the growth, regeneration and stability of our cells, for example in muscles, internal organs and the brain,” explains Safarian. “In addition, choline is involved in fat metabolism and detoxification by the liver. Our body also needs it to produce the neurotransmitter acetylcholine, which is essential for our nervous system and is needed by our brain to control organs. So , you can imagine that malfunctioning FLVCR proteins can cause severe neurological and muscular disorders.”

The researchers used microscopic, biochemical and computational methods to investigate FLVCR proteins. “We froze the proteins and then observed them under an electron microscope,” explains Di Wu, researcher at the Max Planck Institute for Biophysics and co-author of the study. “An electron beam penetrates the frozen sample and the interaction of the electrons with the material creates an image.” Researchers take many individual images and computationally process and combine them to obtain high-resolution 3D structures of proteins. In this way, they were able to decipher the structures of FLVCR1 and FLVCR2 and see how they change in the presence of ethanolamine and choline. Computer simulations confirmed and visualized how FLVCR proteins interact with ethanolamine and choline and dynamically change their structure to enable nutrient transport.

Safarian summarizes: “Our findings open the way to understanding the development and progression of rare diseases associated with FLVCR proteins. In the future, patients may be able to benefit from new therapies that restore their quality of life.”