UCH-L1 in Membranous Nephropathy: Ways to Disease Progression

• Applicant: Professorin Dr. Catherine Meyer-Schwesinger
• Subject Area: Nephrology ; Anatomy and Physiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 550366178

Membranous nephropathy (MN) is the most common cause of adult nephrotic syndrome, an autoimmune disease targeting glomerular podocytes. MN is caused by circulating autoantibodies directed against podocyte foot process antigens such as THSD7A. THSD7A autoantibodies are sufficient to cause MN. Injured podocytes exhibit a de novo expression of the neuronal deubiquitinating enzyme UCH-L1 in podocytes. UCH-L1 protein is modified by oxidative stress in MN, rendering the protein non-functional and prone to engage aberrant interactions i.e. with the proteasome. As podocytes strongly depend on proteasome functionality not only for the removal of aggrieved proteins but also for the orchestration of plasma membrane processes such as endocytosis, the proteasome impairment induced by an aberrant interaction with non-functional UCH-L1 exacerbates MN. As a new pathophysiologic process in MN, podocytes release proteotoxic waste including UCH-L1 and impaired proteasomes via extracellular vesicles, called exophers. MN patients with poor outcome exhibit autoantibodies with preferential reactivity to non-functional UCH-L1 of unknown pathophysiologic significance. We hypothesize that these 'secondary' UCH-L1 autoantibodies aggravate podocyte injury in MN. The overarching aim of the project proposal is to unravel, how UCH-L1 antibodies affect clinical and morphological MN, differentiating between antigen-specific and/or antigen-unspecific mechanisms. For these experiments we will rely on our established mouse models of podocyte-specific modified UCH-L1 expression (Uchl1 pod, Uchl1WT-Oepod, Uchl1I93M-Oepod), our antigen-specific passive and active THSD7A-MN models, and THSD7A-overexpressing human podocytes as well as murine primary podocytes. Specifically, we will 1. investigate the pathogenicity of UCH-L1 (auto)antibodies in murine THSD7A-MN; 2. generate and validate poly- and monoclonal antibodies to non-functional UCH-L1 for in-depth pathophysiologic and translational studies in patient biopsies; 3. unravel the effect of patient UCH-L1 autoantibodies on UCH-L1 function. Overall, the anticipated results will give us actionable knowledge about the pathophysiologic significance of UCH-L1 autoantibodies and their diagnostic / prognostic potential in MN.

• DFG Programme: Research Grants