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

Abstract

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>UCHL1</jats:italic> leads to neuronal insulin resistance and T2D-related symptoms in <jats:italic>Drosophila</jats:italic>. Furthermore, loss of <jats:italic>UCHL1</jats:italic> induces DSN-like phenotypes, including numbness to external noxious stimuli and axonal degeneration of sensory neurons in flies’ legs. Conversely, <jats:italic>UCHL1</jats:italic> 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.</jats:p>