CYLD deficiency causes auditory neuropathy due to reduced neurite outgrowth

Abstract

Background Auditory neuropathy is a cause of hearing loss that has been studied in a number of animal models. Signal transmission from hair cells to spiral ganglion neurons plays an important role in normal hearing. CYLD is a microtubule‐binding protein, and deubiquitinase involved in the regulation of various cellular processes. In this study, we used Cyld knockout (KO) mice and nerve cell lines to examine whether CYLD is associated with auditory neuropathy. Methods Hearing of Cyld KO mice was studied using the TDT RZ6 auditory physiology workstation. The expression and localization of CYLD in mouse cochlea and cell lines were examined by RT‐PCR, immunoblotting, and immunofluorescence. CYLD expression was knocked down in SH‐SY5Y cells by shRNAs and in PC12 and N2A cells by siRNAs. Nerve growth factor and retinoic acid were used to induce neurite outgrowth, and the occurrence and length of neurites were statistically analyzed between knockdown and control groups. Results Cyld KO mice had mild hearing impairment. Moreover, CYLD was widely expressed in mouse cochlear tissues and different nerve cell lines. Knocking down CYLD significantly reduced the length and proportion of neurites growing from nerve cells. Conclusions The abnormal hearing of Cyld KO mice might be caused by a decrease in the length and number of neurites growing from auditory nerve cells in the cochlea, suggesting that CYLD is a key protein affecting hearing.

Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum

“…Posttranslational protein modification by ubiquitin provides a plethora of distinct signals that have emerged as key regulators of neuronal activity, including postsynaptic function and plasticity ( Mabb and Ehlers, 2010 ; Kantamneni et al, 2011 ). Ubiquitination by E3 ubiquitin ligases can be reversed by deubiquitinases (DUBs), while deregulation of DUBs has dramatic physiological consequences and causes a variety of diseases such as neurodegeneration or inflammatory disease ( Palazon-Riquelme et al, 2018 ; Yang et al, 2021 ). Targeted deubiquitination via engineered DUBs corrects ion channelopathies caused by trafficking-deficient ion channels ( Kanner et al, 2020 ).…”

“…In addition, mouse hippocampal neurons transfected with CYLD M719V show a significantly increased cytoplasmic localization of transactivator regulatory DNA-binding protein 43 (TDP-43) and decreased axonal length ( Dobson-Stone et al, 2020 ). CYLD deficiency causes impaired fear memory, auditory neuropathy, and cognitive inflexibility ( Li et al, 2021 ; Yang et al, 2021 ; Zajicek et al, 2022 ).…”

Transdermal Delivery of Polymeric Nanoparticles Containing Aconite Root for the Treatment of Chemotherapy‐Induced Peripheral Neuropathy

“…This observation serves to validate the neurotoxic impact of PTX on PC12 cells (Figure S2B, Supporting Information). [52,53] Accordingly, it was decided to conduct an additional experiment using 10 μM PTX, and the differentiated cells were treated with 10 μM PTX and AR extract, PLGA/AR NPs, and HA-PLGA/AR NPs, respectively. In the case of AR extract and AR PLGA NPs, neurites were about twice as long as when treated with 10 μM PTX and measured about 30-40 μm.…”

CYLD inhibits osteoclastogenesis to ameliorate alveolar bone loss in mice with periodontitis

“…In addition, CYLD participates in regulating a large variety of cell processes, including cell cycle progression, cell migration, chemotherapy drug sensitivity, and ciliogenesis (Hu et al, 2022; Ran et al, 2021; Yang & Zhou, 2016; Yang, Chen, et al, 2021). Cyld knockout (KO) mice exhibited exacerbated hearing impairment and cardiac mortality (Xie et al, 2022; Yang, Ma, et al, 2021). Accumulating evidence has revealed that CYLD acts as a pivotal negative regulator of RANK signaling on preosteoclasts, inhibiting ubiquitination of the E3‐ubiquitin ligase TRAF6 and activating downstream signaling pathways (Asagiri & Takayanagi, 2007; Boyle et al, 2003; Durán et al, 2004; Teitelbaum & Ross, 2003).…”