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

  • Nat Commun. 2024 Jan 11;15(1):468. doi: 10.1038/s41467-024-44747-9.
Daewon Lee  #  1  2 ,  Eunju Yoon  #  1  2 ,  Su Jin Ham  #  1  2 ,  Kunwoo Lee  3 ,  Hansaem Jang  4 ,  Daihn Woo  1 ,  Da Hyun Lee  1  2 ,  Sehyeon Kim  1  2 ,  Sekyu Choi  5  6 ,  Jongkyeong Chung  7  8
Affiliations
  • 1. Institute of Molecular Biology and Genetics, Seoul National University, Seoul, 08826, Republic of Korea.
  • 2. School of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
  • 3. School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea.
  • 4. Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea.
  • 5. School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea. [email protected].
  • 6. Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea. [email protected].
  • 7. Institute of Molecular Biology and Genetics, Seoul National University, Seoul, 08826, Republic of Korea. [email protected].
  • 8. School of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 38212312 DOI: 10.1038/s41467-024-44747-9
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.

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