Chelban Viorica, Manole Andreea, Pihlstrøm Lasse, Schottlaender Lucia, Efthymiou Stephanie, OConnor Emer, Meissner Wassilios G, Holton Janice L, Houlden Henry
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Department of Neurology, Medical and Pharmaceutical State University N. Testemitanu, Chisinau, Moldova.
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Neurobiol Aging. 2017 Jan;49:216.e15-216.e18. doi: 10.1016/j.neurobiolaging.2016.09.021. Epub 2016 Oct 3.
Neurodegenerative diseases are a very diverse group of disorders but they share some common mechanisms such as abnormally misfolded proteins with prion-like propagation and aggregation. Creutzfeldt-Jakob disease (CJD) is the most prevalent prion disease in humans. In the sporadic form of CJD the only known risk factor is the codon 129 polymorphism. Recent reports suggested that α-synuclein in multiple system atrophy (MSA) has similar pathogenic mechanisms as the prion protein. Here we present 1 Italian family with MSA and prion disease. Also, cases of concurrent MSA and prion pathology in the same individual or family suggest the possibility of molecular interaction between prion protein and α-synuclein in the process of protein accumulation and neurodegeneration, warranting further investigations. We assessed the PRNP gene by whole-exome sequencing in 264 pathologically confirmed MSA cases and 462 healthy controls to determine whether the 2 diseases share similar risk factors. We then analyzed codon 129 polymorphism by Sanger sequencing and compared with previously published results in sporadic CJD. Homozygosity at codon 129 was present in 50% of pathologically confirmed MSA cases and in 58% of normal controls (odds ratio, 0.7 (95% confidence interval of 0.5-0.9)) compared with 88.2% in sporadic CJD. Our data show that the homozygous state of position 129 in the PRNP is not a risk factor for MSA. No other variants in the PRNP gene were associated with increased risk for MSA.
神经退行性疾病是一组非常多样的疾病，但它们具有一些共同机制，如异常错误折叠的蛋白质具有朊病毒样的传播和聚集。克雅氏病（CJD）是人类中最常见的朊病毒疾病。在散发性CJD中，唯一已知的风险因素是密码子129多态性。最近的报告表明，多系统萎缩（MSA）中的α-突触核蛋白具有与朊病毒蛋白相似的致病机制。在此，我们报告1个患有MSA和朊病毒疾病的意大利家庭。此外，同一个体或家庭中同时存在MSA和朊病毒病理的病例表明，在蛋白质积累和神经退行性变过程中，朊病毒蛋白和α-突触核蛋白之间可能存在分子相互作用，值得进一步研究。我们通过全外显子测序评估了264例经病理确诊的MSA病例和462例健康对照中的PRNP基因，以确定这两种疾病是否具有相似的风险因素。然后，我们通过桑格测序分析了密码子129多态性，并与散发性CJD中先前发表的结果进行了比较。与散发性CJD中的88.2%相比，经病理确诊的MSA病例中有50%存在密码子129纯合子，正常对照中有58%存在密码子129纯合子（优势比为0.7（95%置信区间为0.5 - 0.9））。我们的数据表明，PRNP中129位的纯合状态不是MSA的风险因素。PRNP基因中没有其他变异与MSA风险增加相关。
