Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss.
Adelaida M CelayaIsabel Sánchez-PérezJose M Bermúdez-MuñozLourdes Rodríguez-de la RosaLaura Pintado-BerninchesRosario PeronaSilvia Murillo-CuestaIsabel Varela-NietoPublished in: eLife (2019)
Mitogen-activated protein kinases (MAPK) such as p38 and the 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. By 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 dysregulated expression of cytokines. These data suggest that DUSP1 is essential for cochlear homeostasis in the response to stress during ageing.
Keyphrases
- hearing loss
- cell death
- inflammatory response
- clinical trial
- signaling pathway
- multiple sclerosis
- induced apoptosis
- poor prognosis
- magnetic resonance
- oxidative stress
- skeletal muscle
- adipose tissue
- machine learning
- dna methylation
- type diabetes
- transcription factor
- computed tomography
- climate change
- randomized controlled trial
- insulin resistance
- risk assessment
- heat stress
- stress induced
- cell proliferation
- metabolic syndrome
- open label
- genome wide
- tyrosine kinase
- artificial intelligence
- high fat diet induced
- genome wide identification
- phase iii
- human health
- double blind