Implications of the serine protease HTRA1 in Light Chain Amyloidosis

• Applicants: Dr. Alexander Carpinteiro; Professor Dr. Michael Ehrmann
• Subject Area: Biochemistry
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 448549772

The widely conserved human serine protease HTRA1 functions as a protein quality control factor by performing conformation specific proteolysis of misfolded or fragmented proteins. Accordingly, previous work has shown that HTRA1 colocalises with amyloid fibrils in cells as well as in the brains of Alzheimer's disease patients. Moreover, HTRA1 efficiently dissociates amyloid fibrils composed of tau or the A peptide for subsequent proteolytic degradation. To obtain evidence for a potentially general role of HTRA1 in protein folding diseases, this research proposal addresses the question of HTRA1's involvement in another severe disease, light chain amyloidosis. Here, hyperproliferating clonogenic plasma cells produce vast amounts of monoclonal immunoglobulin light chains that form extracellular amyloid fibrils. Light chain amyloidosis is a systemic disease where fibrils present in serum deposit at critical organs such as the heart, liver or kidney causing severe organ damage and ultimately a dramatic reduction of life span. To obtain mechanistic insights into HTRA1-dependent fibril dissociation and proteolysis at high temporal and spatial resolution, the investigation will consist of an integrated approach involving protein biochemistry, single molecule analytics, time resolved mass spectrometry, spotted peptide arrays, affinity measurements, computational modelling and cell biological methods. Following safety studies of therapeutically applied HTRA1, we aim at testing the efficacy of HTRA1 in resolving amyloid deposits in a mouse model of amyloidosis.

• DFG Programme: Research Grants