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Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila

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Listed:
  • Daewon Lee

    (Seoul National University
    Seoul National University)

  • Eunju Yoon

    (Seoul National University
    Seoul National University)

  • Su Jin Ham

    (Seoul National University
    Seoul National University)

  • Kunwoo Lee

    (Pohang University of Science and Technology)

  • Hansaem Jang

    (Pohang University of Science and Technology)

  • Daihn Woo

    (Seoul National University)

  • Da Hyun Lee

    (Seoul National University
    Seoul National University)

  • Sehyeon Kim

    (Seoul National University
    Seoul National University)

  • Sekyu Choi

    (Pohang University of Science and Technology
    Pohang University of Science and Technology)

  • Jongkyeong Chung

    (Seoul National University
    Seoul National University)

Abstract

Diabetic sensory neuropathy (DSN) is one of the most common complications of type 2 diabetes (T2D), however the molecular mechanistic association between T2D and DSN remains elusive. Here we identify ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinase highly expressed in neurons, as a key molecule underlying T2D and DSN. Genetic ablation of UCHL1 leads to neuronal insulin resistance and T2D-related symptoms in Drosophila. Furthermore, loss of UCHL1 induces DSN-like phenotypes, including numbness to external noxious stimuli and axonal degeneration of sensory neurons in flies’ legs. Conversely, UCHL1 overexpression improves DSN-like defects of T2D model flies. UCHL1 governs insulin signaling by deubiquitinating insulin receptor substrate 1 (IRS1) and antagonizes an E3 ligase of IRS1, Cullin 1 (CUL1). Consistent with these results, genetic and pharmacological suppression of CUL1 activity rescues T2D- and DSN-associated phenotypes. Therefore, our findings suggest a complete set of genetic factors explaining T2D and DSN, together with potential remedies for the diseases.

Suggested Citation

  • Daewon Lee & Eunju Yoon & Su Jin Ham & Kunwoo Lee & Hansaem Jang & Daihn Woo & Da Hyun Lee & Sehyeon Kim & Sekyu Choi & Jongkyeong Chung, 2024. "Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44747-9
    DOI: 10.1038/s41467-024-44747-9
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    References listed on IDEAS

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