Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss
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.
-
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
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.
Reviewing Editor
- Christine Petit, Institut Pasteur, France
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.
Version history
- Received: June 12, 2018
- Accepted: April 1, 2019
- Accepted Manuscript published: April 2, 2019 (version 1)
- Version of Record published: April 15, 2019 (version 2)
- Version of Record updated: June 7, 2019 (version 3)
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.
Metrics
-
- 2,253
- Page views
-
- 294
- Downloads
-
- 18
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.
-
- Cell Biology
- Neuroscience
Despite decades of intense study, the molecular basis of asynchronous neurotransmitter release remains enigmatic. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses, Doc2α is the major Ca2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2α, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot be replenished on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse onward during repetitive activity. By contrast, synapses lacking Doc2α have normal activity-dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus providing synaptic vesicles for synchronous (syt1) and asynchronous (Doc2 and other unidentified sensors) release during ongoing transmission.