Analyses of splice- and risk variant dependent pathomechanisms for APOL1

• Applicant: Professor Dr. Thomas Weide
• Subject Area: Nephrology
• Term: from 2017 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 324783603

Apolipoprotein (APOL1) was initially identified as trypanolytic factor in human serum. Here, it protects humans against subspecies of the parasite Trypanosoma brucei, which causes African sleeping sickness (also called Human African Trypanosomiasis). Intriguingly, similar to the link between sickle cell anemia and human resistance to malaria, the protection against parasites is linked to an increased risk for a disease. Because analyses of the last years demonstrated that some APOL1 allelic variants (renal risk variants) are linked to non-inherited forms of focal-segmental glomerulosclerosis (FSGS) as well as to HIV-, hypertension-, and – as recently shown ¬ – Covid-19 associated diseases.APOL1 is only expressed in humans and some higher primates and the underlying cytopathic effects of APOL1 are still incompletely understood. Among other mechanisms, there is some evidence that APOL1 causes mitochondria dysfunction, an altered ion flux across the plasma membrane, or ER stress. In addition, APOL1 is expressed in different splice variants that are associated with two different orientations (or insertions) into intracellular membranes. Our preceding work demonstrated that both orientations (cis and trans) are linked with cytotoxic effects. This observation suggests that APOL1 cytotoxicity depends on several factors, including the presence of risk variant alleles, the intracellular expression level, and the ratio between cis and trans oriented splice variants.In this project, we will investigate the pathogenic potential of individual splice- and risk variant combinations and analyze how these combinations correlate with pathomechanisms (e. g. Mitochondria dysfunction, or ER stress). Moreover, we will search for molecules and compounds that are either able to inhibit toxic APOL1 functions or that can trigger an enhanced ubiquitin-proteasome-dependent APOL1 degradation.

• DFG Programme: Research Grants