Optineurin inclusions occur in a minority of TDP-43 positive ALS and FTLD-TDP cases and are rarely observed in other neurodegenerative disorders
Optineurin inclusions occur in a minority of TDP-43 positive ALS and FTLD-TDP cases and are rarely observed in other neurodegenerative disorders
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DOI：
10.1007/s00401-011-0813-3
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发表时间：
2011-04-01
影响因子：
12.7
通讯作者：
Shaw, Christopher E.
中科院分区：
文献类型：
--
作者：
Hortobagyi, Tibor;Troakes, Claire;Shaw, Christopher E.
视神经磷酸酶(optineurin，OPTN)是一种多功能蛋白，参与囊泡运输、信号转导和基因表达。报道了8例家族性和散发性肌萎缩侧索硬化症(FALS，SALS)日本患者的OPTN突变。与TDP-43共同定位的OPTN阳性包涵体在SALS和FALS中被描述为具有SOD-1突变，潜在地连接了运动神经元变性的两条不同的病理途径。我们用一系列抗体研究了138例死后组织中OPTN包涵体的丰度，包括散发性和家族性肌萎缩侧索硬化症、额颞叶变性(FTLD)和多种神经变性蛋白病。OPTN阳性包涵体不常见，仅在TDP-43阳性的SALS脊髓中11/32(34%)和FTLD-TDP中的5/15(33%)中检测到。来自FTLD-TDP额叶皮质和TDP-43阳性SALS脊髓的裂解产物的Western印迹显示，与对照组相比，OPTN蛋白水平降低(p<；0.05)，然而，这与大脑中神经元数量的减少有关。在分别存在SOD-1和FUS突变的FAL和FTLD-FUS病例中未检测到大的OPTN包涵体。在少数阿尔茨海默病(AD)病例中发现了OPTN阳性包涵体，但未与tau和TDP-43共同定位。在亨廷顿病(HD)中偶见纹状体神经元呈颗粒状胞浆OPTN免疫阳性，而在脊髓小脑性共济失调3型中未见OPTN免疫阳性反应。FTLD-tau病和α-突触核病中未检测到OPTN包涵体。我们的结论是，OPTN包涵体相对罕见，主要限于少数TDP-43阳性的ALS和FTLD-TDP病例。我们的结果不支持OPTN包涵体在ALS、FTLD或任何其他神经退行性疾病的发病机制中发挥核心作用的命题。
Optineurin (OPTN) is a multifunctional protein involved in vesicular trafficking, signal transduction and gene expression. OPTN mutations were described in eight Japanese patients with familial and sporadic amyotrophic lateral sclerosis (FALS, SALS). OPTN-positive inclusions co-localising with TDP-43 were described in SALS and in FALS with SOD-1 mutations, potentially linking two pathologically distinct pathways of motor neuron degeneration. We have explored the abundance of OPTN inclusions using a range of antibodies in postmortem tissues from 138 cases and controls including sporadic and familial ALS, frontotemporal lobar degeneration (FTLD) and a wide range of neurodegenerative proteinopathies. OPTN-positive inclusions were uncommon and detected in only 11/32 (34%) of TDP-43-positive SALS spinal cord and 5/15 (33%) of FTLD-TDP. Western blot of lysates from FTLD-TDP frontal cortex and TDP-43-positive SALS spinal cord revealed decreased levels of OPTN protein compared to controls (p < 0.05), however, this correlated with decreased neuronal numbers in the brain. Large OPTN inclusions were not detected in FALS with SOD-1 and FUS mutation, respectively, or in FTLD-FUS cases. OPTN-positive inclusions were identified in a few Alzheimer's disease (AD) cases but did not co-localise with tau and TDP-43. Occasional striatal neurons contained granular cytoplasmic OPTN immunopositivity in Huntington's disease (HD) but were absent in spinocerebellar ataxia type 3. No OPTN inclusions were detected in FTLD-tau and alpha-synucleinopathy. We conclude that OPTN inclusions are relatively rare and largely restricted to a minority of TDP-43 positive ALS and FTLD-TDP cases. Our results do not support the proposition that OPTN inclusions play a central role in the pathogenesis of ALS, FTLD or any other neurodegenerative disorder.