Sha Su-Hua, Chen Fu-Quan, Schacht Jochen
Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Hear Res. 2010 Jun 1;264(1-2):86-92. doi: 10.1016/j.heares.2009.09.002. Epub 2009 Sep 15.
We have previously reported the activation of cell death pathways in the sensory cells of the aging cochlea. Here we investigate age-associated changes in survival mechanisms focusing on phosphatidylinositol 3,4,5-trisphosphate (PIP(3))/Akt signaling. The animal model is the CBA/J mouse of 18 months of age prior to the onset of major functional loss (ABR thresholds, 26+/-8 dB SPL) which is compared to young animals of 3 months of age (ABR thresholds, 19+/-7 dB SPL). Immunostaining on cochlear cryosections revealed a wide-spread distribution of PIP(3) in the cochlea which was markedly attenuated in old animals in inner and outer hair cells, Deiters cells and pillar cells. Protein levels of the lipid phosphatase PTEN which regulates PIP(3) increased in those cells with aging while its mRNA did not, suggesting an age-related reduction of PTEN degradation. Furthermore, staining intensity of phosphorylated PTEN (ser380) and its nuclear localization increased. Consistent with a reduction of PIP(3), the phosphorylation of the downstream target Akt at threonine 308 significantly decreased in outer hair cells. The results suggest a decline of the survival capacity of aging outer hair cells due to a decrease in PIP(3)/Akt signaling caused by an increase of PTEN.
我们之前报道过衰老耳蜗感觉细胞中细胞死亡途径的激活。在此，我们聚焦于磷脂酰肌醇3,4,5-三磷酸（PIP(3)）/Akt信号传导，研究与年龄相关的生存机制变化。动物模型为18月龄的CBA/J小鼠，此时尚未出现主要功能丧失（听性脑干反应阈值，26±8 dB SPL），并将其与3月龄的年轻动物（听性脑干反应阈值，19±7 dB SPL）进行比较。对耳蜗冰冻切片进行免疫染色显示，PIP(3)在耳蜗中广泛分布，而在老年动物的内、外毛细胞、Deiters细胞和柱细胞中显著减弱。调节PIP(3)的脂质磷酸酶PTEN的蛋白水平在这些细胞中随衰老而增加，而其mRNA水平未增加，这表明与年龄相关的PTEN降解减少。此外，磷酸化PTEN（ser380）的染色强度及其核定位增加。与PIP(3)减少一致，外毛细胞中下游靶点Akt在苏氨酸308处的磷酸化显著降低。结果表明，由于PTEN增加导致PIP(3)/Akt信号传导减少，衰老外毛细胞的生存能力下降。
