PDF(Pubmed)
Abstract：
Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.
摘要：
显性视神经萎缩（DOA）是遗传性视神经病变的最普遍形式之一，主要由OPA1中的杂合变体引起，编码线粒体动力蛋白相关的大GTP酶。DOA的临床范围已经扩展到各种各样的综合征表现，叫做DOAPLUS,包括耳聋作为与视力障碍相关的主要次要症状。迄今为止,DOA中耳聋的病理生理机制尚不清楚。为了深入了解导致听力障碍的过程，我们分析了Opa1delTTAG小鼠模型，该模型通过结合形态生理学的补充方法概括了DOAplus综合征，生物化学,细胞和分子生物学。我们发现Opa1delTTAG突变导致小鼠成年发作的进行性听觉神经病,听觉脑干反应阈值随时间的变化证明了这一点。然而,与野生型同窝动物相比，突变小鼠具有更大的耳声发射，而耳蜗内电位，它是血管纹功能状态的代表，两种基因型之间具有可比性。对突变小鼠的超微结构检查显示感觉内部毛细胞的选择性丧失，以及螺旋神经节神经元传入末端的轴突和髓鞘的进行性变性，支持听觉神经病变谱系障碍（ANSD）。耳蜗的分子评估表明Opa1mRNA水平降低了40％以上，支持单倍体功能不全作为疾病机制。此外,我们证明了Sirtuin3水平和Beclin1活性的早期增加，随后与年龄相关的mtDNA消耗，氧化应激增加，线粒体自噬以及自噬通量受损。一起,这些结果支持OPA1在维持内部毛细胞和听觉神经结构中的新作用，解决OPA1相关ANSD患者探索和治疗的新挑战。
