New DFG Research Unit for Ulm University: Over the next three years, researchers led by Professor Marcus Fändrich, Director of the Institute of Protein Biochemistry, will take a close look at systemic amyloidosis. This disease has many faces. If the heart or kidneys are affected, it can lead to death after only a few months when left untreated. Equipped with more than 2.1 million euros in funding, the scientists from Ulm, Erlangen, Munich, Heidelberg and Kiel set out to identify which protein biochemical factors lead to the development of the disease as well as the different manifestations of amyloidosis. Their future results will not only serve basic research: In the long term, they could improve early diagnosis and consequently the care of affected patients.

In systemic amyloidosis, the body's own pathologically altered proteins accumulate in the tissue or in organs such as the heart and kidneys. These deposits lead to malfunctions and even organ failure. There are great variations in the amount of amyloid deposits and the course of the disease: Each of the approximately 250 patients diagnosed each year at the Amyloidosis Centre of the University Hospital in Heidelberg shows an individual clinical picture. The most common form, known as light-chain or AL amyloidosis, which is the main focus of the Research Unit, is often very aggressive: An organ transplant may become necessary shortly after onset of the illness.

The pathogenesis of the condition is not yet fully understood. The cause is thought to be a misfolding of the so-called antibody light chains, which then leads to the characteristic deposits in the tissue. This pathological process is observed, for example, in cancer patients with multiple myeloma. But why is it that only five percent of all patients with such a pre-existing condition develop AL amyloidosis? And what causes such varied clinical pictures? These are the key questions the new Research Unit 2969 'Mechanisms of misfolding of the antibody light chains in systemic AL amyloidosis' will tackle, utilising a broad spectrum of biochemical methods. They also have cutting-edge imaging techniques such as MALDI imaging and cryo-electron microscopy at their disposal. It is still unclear why the amyloid deposits manifest so differently and why the disease affects primarily the heart in one case and the kidneys in another. The mechanisms underlying the misfolding of the light chains and the interplay between the deposits and tissues are also largely misunderstood. 'Although AL amyloidosis is relatively rare, it is considered the archetype of a patient-specific protein misfolding disease. A deeper understanding of the underlying protein biochemical principles is a prerequisite for the development of new treatment approaches,' explains Professor Marcus Fändrich, spokesperson of the DFG Research Unit.

The scientists from medicine and life sciences assume that the different clinical pictures of AL amyloidosis are determined by the high degree of variability of natural light chains and thus by different protein properties. To test this hypothesis, the researchers are analysing blood, kidney and heart tissue as well as bone marrow and fat from patients. The goal is to correlate characteristics of the extracted amyloid deposits with disease severity and affected organs. Ulm University affords the Research Unit the expertise of the Institute of Protein Biochemistry: Using cryogenic electron microscopy, the Fändrich group will investigate the structure of amyloid fibrils from the heart tissues of affected patients, while Dr. Christian Haupt, in close cooperation with doctors at the Amyloidosis Centre in Heidelberg, will compare the variability of pathological amyloid fibrils in patients who are primarily affected in either the heart or the kidneys. The aim is to draw possible conclusions about the development of the different clinical pictures. 'Another mission of the Research Unit, which is unique worldwide in its orientation, is to make the relatively rare disease and its research efforts known to a wider public,' the scientists explained.

Researchers from the Universities of Kiel, Erlangen-Nuremberg, Heidelberg and the Technical University of Munich (TUM) are also part of the Unit.
A DFG Research Unit is a working alliance of outstanding scientists dedicated to a topical research task. The collaboration is initially planned for three years, followed by a new assessment and, if successful, a second funding period. Besides achieving excellence in science, the Research Unit also aims to promote young scientists.

Text and media contact: Annika Bingmann