Do secondary mitochondrial DNA defects cause retinal ganglion cell death in dominant optic atrophy?

显性视神经萎缩（DOA）是遗传性失明的最常见形式之一，它会导致严重的视力残疾。DOA是由视神经的不可逆损伤引起的，视神经连接眼睛和大脑内的视觉中心。它是一种由大约200万个高度专业化的细胞组成的特殊电缆，称为视网膜神经节细胞（RGC）。在60-70%的病例中，DOA是由于OPA 1基因突变引起的，但我们仍然不知道这种遗传缺陷如何导致疾病以及为什么只有RGC受到影响。我们在一个DOA大家族中的初步发现表明OPA 1突变损害了线粒体的正常功能。线粒体是所有人类细胞的基本组成部分，它们负责能量生产。如果产生的能量不足，细胞就不能正常工作并死亡。为了进一步验证我的假设，我将分析来自其他DOA家族的血液和肌肉活检，以寻找线粒体功能障碍的证据。我还将分析来自DOA小鼠模型的RGC，并确定它们是否含有高水平的线粒体DNA异常。最后，我将尝试确定那些没有携带OPA 1突变的家庭中负责DOA的基因。RGC在青光眼等其他眼部疾病中也会受到影响，更好地了解它们的选择性脆弱性将有助于我们为这些致盲疾病制定更有效的治疗策略。

Dominant optic atrophy (DOA) is one of the commonest form of inherited blindness and it results in significant visual disability. DOA is caused by irreversible damage to the optic nerve, which connects the eye to the vision centres within the brain. It is a specialised cable made up of about 2 million, highly specialised cells known as retinal ganglion cells (RGCs). In 60-70% of cases, DOA is due to a mutation in the OPA1 gene but we still do not know how this genetic defect leads to disease and why only RGCs are affected. Our preliminary findings in one large family with DOA indicate that the OPA1 mutation compromises the normal function of mitochondria. Mitochondria are essential components of all human cells and they are responsible for energy production. If insufficient energy is produced, cells cannot function properly and die. To test my hypothesis further, I will analyse blood and muscle biopsies from additional families with DOA for evidence of mitochondrial dysfunction. I will also analyse RGCs from a mouse model of DOA and determine if they contain high levels of mitochondrial DNA abnormalities. Finally, I will try to identify the gene(s) responsible for DOA in those families who not carry an OPA1 mutation. RGCs are affected in other eye conditions like glaucoma and a better understanding of their selective vulnerability will help us develop more effective treatment strategies for these blinding diseases.