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A SNARE protective pool antagonizes APOL1 renal toxicity in Drosophila nephrocytes
Jin-Gu Lee1,2, Yulong Fu1,3, Jun-Yi Zhu1,2
1Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine (UMSOM), 670 West Baltimore Street, 4052 HSFIII, Baltimore, MD, 21201, USA.
Insights
SNARE proteins protect against kidney damage caused by APOL1 gene variants common in people of African ancestry. These proteins bind to APOL1, offering a potential new target for treating APOL1-associated chronic kidney disease (CKD).
Area of Science:
- Genetics
- Molecular Biology
- Nephrology
Background:
- Individuals of Sub-Saharan African ancestry have an increased risk of chronic kidney disease (CKD).
- This heightened risk is linked to specific Apolipoprotein L1 (APOL1) gene risk alleles (G1 and G2).
- The precise mechanisms driving APOL1-related CKD are not fully understood, impeding treatment development.
Purpose of the Study:
- To identify genetic factors that modify the toxicity of APOL1 risk alleles.
- To uncover potential therapeutic targets for APOL1-associated nephropathies.
Main Methods:
- A Drosophila genetic modifier screen was employed to identify proteins influencing APOL1 cytotoxicity.
- The binding affinity of SNARE proteins to different APOL1 variants was assessed.
- The impact of SNARE protein expression levels on APOL1 toxicity in fly nephrocytes was evaluated.
Main Results:
- SNARE proteins (Syx7, Ykt6, and Syb) were identified as key players in mitigating APOL1 cytotoxicity.
- Reduced expression of these SNARE proteins exacerbated APOL1 toxicity in fly nephrocytes.
- Overexpression of Syx7, Ykt6, or Syb attenuated APOL1 toxicity.
- These SNARE proteins demonstrated higher binding affinity for APOL1-G0 compared to APOL1 risk alleles (G1/G2).
Conclusions:
- SNARE proteins (Syx7, Ykt6, and Syb) act as antagonists to APOL1-induced cytotoxicity through direct binding.
- This study reveals a protective role for specific SNARE proteins in the context of APOL1-CKD pathogenesis.
- These findings present novel therapeutic targets for APOL1-associated kidney diseases.
Background:
People of Sub-Saharan African ancestry are at higher risk of developing chronic kidney disease (CKD), attributed to the Apolipoprotein L1 (APOL1) gene risk alleles (RA) G1 and G2. The underlying mechanisms by which the APOL1-RA precipitate CKD remain elusive, hindering the development of potential treatments.
Results:
Using a Drosophila genetic modifier screen, we found that SNARE proteins (Syx7, Ykt6, and Syb) play an important role in preventing APOL1 cytotoxicity. Reducing the expression of these SNARE proteins significantly increased APOL1 cytotoxicity in fly nephrocytes, the equivalent of mammalian podocytes, whereas overexpression of Syx7, Ykt6, or Syb attenuated their toxicity in nephrocytes. These SNARE proteins bound to APOL1-G0 with higher affinity than APOL1-G1/G2, and attenuated APOL1-G0 cytotoxicity to a greater extent than either APOL1-RA.
Conclusions:
Using a Drosophila screen, we identified SNARE proteins (Syx7, Ykt6, and Syb) as antagonists of APOL1-induced cytotoxicity by directly binding APOL1. These data uncovered a new potential protective role for certain SNARE proteins in the pathogenesis of APOL1-CKD and provide novel therapeutic targets for APOL1-associated nephropathies.
