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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Distinct sets of lysosomal genes define synucleinopathy and tauopathy

  • Kyu Won Oh (Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine) ;
  • Dong-Kyu Kim (Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine) ;
  • Ao-Lin Hsu (Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University) ;
  • Seung-Jae Lee (Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine)
  • Received : 2023.06.27
  • Accepted : 2023.09.11
  • Published : 2023.12.31
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Abstract

Neurodegenerative diseases are characterized by distinct protein aggregates, such as those of α-synuclein and tau. Lysosomal defect is a key contributor to the accumulation and propagation of aberrant protein aggregates in these diseases. The discoveries of common proteinopathies in multiple forms of lysosomal storage diseases (LSDs) and the identification of some LSD genes as susceptible genes for those proteinopathies suggest causative links between LSDs and the proteinopathies. The present study hypothesized that defects in lysosomal genes will differentially affect the propagation of α-synuclein and tau proteins, thereby determining the progression of a specific proteinopathy. We established an imaging-based high-contents screening (HCS) system in Caenorhabditis elegans (C. elegans) model, by which the propagation of α-synuclein or tau is measured by fluorescence intensity. Using this system, we performed RNA interference (RNAi) screening to induce a wide range of lysosomal malfunction through knock down of 79 LSD genes, and to obtain the candidate genes with significant change in protein propagation. While some LSD genes commonly affected both α-synuclein and tau propagation, our study identified the distinct sets of LSD genes that differentially regulate the propagation of either α-synuclein or tau. The specificity and efficacy of these LSD genes were retained in the disease-related phenotypes, such as pharyngeal pumping behavior and life span. This study suggests that distinct lysosomal genes differentially regulate the propagation of α-synuclein and tau, and offer a steppingstone to understanding disease specificity.

Keywords

Acknowledgement

This work was supported by National Research Foundation (NRF) grants funded by the Korean Government (MSIT) (NRF-2018R1A5A2025964 to S.-J.L. and 2022R1I1A1A01070958 to D.-K.K.). K.W.O. received a scholarship from the BK21-FOUR education program.

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