Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss
- Institute for Biomedical Research 'Alberto Sols' (CSIC-UAM), Spain
Abstract
Mitogen-activated protein kinases (MAPK) p38 and c-Jun N-terminal kinases (JNKs) are activated during the cellular response to stress signals. Their activity is regulated by the MAPK-phosphatase 1 (DUSP1), a key component of the anti-inflammatory response. Stress kinases are well-described elements of the response to otic injury and the otoprotective potential of JNK inhibitors is being tested in clinical trials. In contrast, there are no studies exploring the role of DUSP1 in hearing and hearing loss. Here we show that Dusp1 expression is age-regulated in the mouse cochlea. Dusp1 gene knock-out caused premature progressive hearing loss, as confirmed by auditory evoked responses in Dusp1-/- mice. Hearing loss correlated with cell death in hair cells, degeneration of spiral neurons and increased macrophage infiltration. Dusp1-/- mouse cochleae showed imbalanced redox status and deregulated expression of cytokines. These data suggest that DUSP1 is essential for cochlear homeostasis in the response to stress during ageing.
Data availability
Source data files have been provided for ABR data in Figures 2 and Figure2-figure supplement 1, as well as for gene expression data in Figures 1, 3, 5, 6 and Figure1-figure supplement 1. Data has also been deposited on Dryad under the doi: 10.5061/dryad.51m8c58.
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Data from: Deficit of mitogen-activated protein kinase phosphatase 1 (MKP1) accelerates progressive hearing lossDryad Digital Repository, doi:10.5061/dryad.51m8c58.
Article and author information
Author details
Isabel Sánchez-Pérez
Jose M Bermúdez-Muñoz
Silvia Murillo-Cuesta
Funding
Ministerio de Economía y Competitividad (SAF2017-86107-R)
- Isabel Varela-Nieto
Federación Española de Enfermedades Raras (P17-01401)
- Isabel Varela-Nieto
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experimentation was conducted in accordance with Spanish (RD 53/2013) and European (Directive 2010/63/EU) legislations. All protocols used in this study were reviewed and approved by the Ethical Committee of Animal Experimentation at IIBm and Ethical Committee at CSIC in a facility inscribed in the official registration of breeding establishments, suppliers and users of experimental animals in the Ministry of Agriculture, Fisheries and Food (registration number, ES280790000188). Mice procedures were done according with scientific, humane, and ethical principles. The studied mouse model did not show phenotype differences comparing male and female. Thus, to ensure that our research represents both genders, the studies describes in this work were performed using both sexes equitably. The number of biological and experimental replicates is detailed in the legend of each figure.
Copyright
© 2019, Celaya et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss
eLife 8:e39159.
https://doi.org/10.7554/eLife.39159
Further reading
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- Neuroscience
Dense core vesicles (DCVs) transport and release various neuropeptides and neurotrophins that control diverse brain functions, but the DCV secretory pathway remains poorly understood. Here, we tested a prediction emerging from invertebrate studies about the crucial role of the intracellular trafficking GTPase Rab10, by assessing DCV exocytosis at single-cell resolution upon acute Rab10 depletion in mature mouse hippocampal neurons, to circumvent potential confounding effects of Rab10’s established role in neurite outgrowth. We observed a significant inhibition of DCV exocytosis in Rab10-depleted neurons, whereas synaptic vesicle exocytosis was unaffected. However, rather than a direct involvement in DCV trafficking, this effect was attributed to two ER-dependent processes, ER-regulated intracellular Ca2+ dynamics, and protein synthesis. Gene Ontology analysis of differentially expressed proteins upon Rab10 depletion identified substantial alterations in synaptic and ER/ribosomal proteins, including the Ca2+ pump SERCA2. In addition, ER morphology and dynamics were altered, ER Ca2+ levels were depleted, and Ca2+ homeostasis was impaired in Rab10-depleted neurons. However, Ca2+ entry using a Ca2+ ionophore still triggered less DCV exocytosis. Instead, leucine supplementation, which enhances protein synthesis, largely rescued DCV exocytosis deficiency. We conclude that Rab10 is required for neuropeptide release by maintaining Ca2+ dynamics and regulating protein synthesis. Furthermore, DCV exocytosis appeared more dependent on (acute) protein synthesis than synaptic vesicle exocytosis.
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- Neuroscience
By influencing calcium homeostasis, local protein synthesis and the endoplasmic reticulum, a small protein called Rab10 emerges as a crucial cytoplasmic regulator of neuropeptide secretion.
