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

Daewon Lee, Eunju Yoon, Su Jin Ham, Kunwoo Lee, Hansaem Jang, Daihn Woo, Da Hyun Lee, Sehyeon Kim, Sekyu Choi () and Jongkyeong Chung ()
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Daewon Lee: Seoul National University
Eunju Yoon: Seoul National University
Su Jin Ham: 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
Sehyeon Kim: Seoul National University
Sekyu Choi: Pohang University of Science and Technology
Jongkyeong Chung: Seoul National University

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-44747-9

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