Analysis of the functional and spatial proteome of cardiac ATTR amyloidosis

• Applicants: Professor Dr. Christoph Röcken; Professor Dr. Andreas Tholey
• Subject Area: Pathology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566846885

Cardiac ATTR amyloidosis (ATTR-CM) has a serious impact on a patient's quality of life due to the development of heart failure and shortens survival time to about 4 years. Our systematic quantification of amyloid burden in heart biopsies of over 400 cases has shown that ATTR amyloid content is variable, ranging from 0.2% to 68.0% of the cross-sectional area (mean 20.6%, median 19%). We propose that (i) amyloidosis is a dynamic disease whose composition and physical appearance changes from the time of formation in the patient to the final stage of the disease. While the fibril protein itself undergoes changes during progression (e.g., through various post-translational modifications), the surrounding amyloid proteome also changes qualitatively and quantitatively. (ii) These changes are expressed in a temporal and spatial manner. Phenotypes of deposits appear with variable composition depending on microanatomical (spatial) distribution and disease stage, e.g., deposits differ between different histological structures (vessel wall vs. interstitium), and small deposits differ from larger ones. (iii) In addition, changes in amyloid deposits can be detected from the interior of the deposit to the interface between the amyloid and the surrounding myocardium. (iv) These changes reflect "functional proteomic stages" in ATTR-CM that impact disease stage, progression, and patient outcome, necessitating proteoform-centric analysis combined with (various) omics that investigate the amyloid nano-environment as a novel approach to amyloid research. Our comprehensive proteomic approach includes bottom-up proteomics, top-down proteomics, terminomics, and is flanked by spatial transcriptomics and extensive validation studies. We aim to decipher the functional proteome and shed light on the disease mechanism in ATTR-CM. The data collected by our study will decipher biological functions of the peptides and proteins associated with ATTR-CM in a spatial and temporal manner. Systems biology evaluations will test the hypothesis that tissue-related and cell-biological processes differ depending on the amount of deposited amyloid, i.e., in the late/advanced stage other cell biological processes determine the disease than in the early/less advanced stage. To the best of our knowledge, an analysis of this kind has not been conducted previously. However, it could have substantial consequences for the diagnosis and treatment of the disease, as it provides significant insights into the temporal dynamics of the disease. The knowledge gained could form the basis to develop novel diagnostic procedures as well as therapy protocols adapted to the stage of disease.

• DFG Programme: Research Grants