MKP1 deficit causes hair cell loss, spiral ganglion degeneration and progressive hearing loss

Abstract

Age-related hearing loss (ARHL) is the most prevalent sensorial impairment of the elderly (WHO, February 2017). Its onset and progression rely on not well-characterized genetic factors, often aggravated by noxious factors such as noise and ototoxic agents. Stress kinases, p38 and JNK, activation precedes cellular loss and its pharmacological inhibition has proved to be otoprotective in animal models. The MAP kinase phosphatases (MKP) are natural regulators of the activity of stress kinases and central elements in the cellular response triggered by these enzymes but their role in hearing loss has not been studied. ABR and DPOAE hearing thresholds were measured, data analysis showed that Mkp1-/- mice suffered premature and progressive hearing loss. Higher ABR latencies of wave I indicated delayed transmission. Functional decline along life correlated with morphological and cellular cochlear alterations. Histological analysis and immunohistochemistry revealed loss of sensory cells in the organ of Corti, degeneration of afferent spiral neurons, loss of the spiral ligament fibrocytes and increased macrophages infiltration. Gene expression data (RNA-Seq and RT-qPCR) confirmed the altered transcriptome profile of null mice, concretely deregulation of GSH biosynthesis and antioxidant enzymes, unbalance of pro- and anti- inflammatory cytokines. In summary, we show here that MKP1 deficiency causes an exacerbated inflammatory response and accelerates progressive hearing loss.