Dataset Information

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

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.

SUBMITTER: Lee D

PROVIDER: S-EPMC10784524 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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

Lee Daewon D Yoon Eunju E Ham Su Jin SJ Lee Kunwoo K Jang Hansaem H Woo Daihn D Lee Da Hyun DH Kim Sehyeon S Choi Sekyu S Chung Jongkyeong J

Nature communications 20240111 1

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 ...[more]

PMID: 38212312

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Project description:PurposeCisplatin is a critical component of first-line chemotherapy for several cancers, but causes peripheral sensory neuropathy, hearing loss, and tinnitus. We aimed to identify comorbidities for cisplatin-induced neurotoxicities among large numbers of similarly treated patients without the confounding effect of cranial radiotherapy.MethodsUtilizing linear and logistic regression analyses on 1680 well-characterized cisplatin-treated testicular cancer survivors, we analyzed associations of hearing loss, tinnitus, and peripheral neuropathy with nongenetic comorbidities. Genome-wide association studies and gene-based analyses were performed on each phenotype.ResultsHearing loss, tinnitus, and peripheral neuropathy, accounting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension and poorer self-reported health. In addition, hearing loss was positively associated with BMIs at clinical evaluation and nonwork-related noise exposure (>5 h/week). Tinnitus was positively associated with tobacco use, hypercholesterolemia, and noise exposure. We observed positive associations between peripheral neuropathy and persistent vertigo, tobacco use, and excess alcohol consumption. Hearing loss and TXNRD1, which plays a key role in redox regulation, showed borderline significance (p = 4.2 × 10-6 ) in gene-based analysis. rs62283056 in WFS1 previously found to be significantly associated with hearing loss (n = 511), was marginally significant in an independent replication cohort (p = 0.06; n = 606). Gene-based analyses identified significant associations between tinnitus and WNT8A (p = 2.5 × 10-6 ), encoding a signaling protein important in germ cell tumors.ConclusionsGenetics variants in TXNRD1 and WNT8A are notable risk factors for hearing loss and tinnitus, respectively. Future studies should investigate these genes and if replicated, identify their potential impact on preventive strategies.

Dataset Information

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

Publications

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

Similar Datasets

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