Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis.
Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis.
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DOI：
10.1002/ana.22149
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发表时间：
2011-01
影响因子：
11.2
通讯作者：
Nath, Avindra
中科院分区：
文献类型：
--
作者：
Douville, Renee;Liu, Jiankai;Rothstein, Jeffrey;Nath, Avindra
肌萎缩侧索硬化症（ALS）的特征在于运动神经元的进行性丧失，病因不明。先前的研究表明，ALS患者血清中的逆转录酶水平与HIV感染患者相当;然而，逆转录病毒成分的来源和意义尚不确定。通过真实的时间聚合酶链反应，随后对扩增的基因进行测序，并通过免疫染色证实，在ALS患者的尸检脑组织中测定人内源性逆转录病毒（HERV-K）的表达，并与对照人群进行比较。与慢性全身性疾病患者相比，ALS患者的HERV-K pol转录物增加，但在帕金森病或意外死亡对照中无法检测到。测序结果显示，HML-2和HERV-K的3个亚家族中有几个活跃转录的基因座，具有特定的表达模式，包括完整的开放阅读框和ALS中独特基因座的转录。完整的pol转录本的频率是最高的运动皮层和逆转录酶蛋白定位于ALS患者的皮层神经元。HERV-K表达与TDP-43密切相关，TDP-43是一种已知在ALS中失调的多功能蛋白质。我们已经确定了ALS中HERV-K表达的特定模式，这可能潜在地定义了ALS的病理生理学。靶向激活的基因组编码的逆转录病毒元件可能为ALS的治疗开辟新的前景。
Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons, of unknown etiology. Previous studies showed reverse transcriptase in serum of ALS patients at levels comparable to HIV-infected patients; however, the source and significance of the retroviral elements is uncertain. Expression of a human endogenous retrovirus (HERV-K), was determined in autopsy brain tissue of patients with ALS and compared to control populations, by real time polymerase chain reaction followed by sequencing of the amplified genes and confirmed by immunostaining. HERV-K pol transcripts were increased in patients with ALS compared to those with chronic systemic illness, but could not be detected in Parkinson’s disease or in the accidental death controls. Sequencing revealed several actively transcribed loci in the HML-2 and 3 subfamilies of HERV-K, with a specific pattern of expression including intact open reading frames and the transcription of a unique locus in ALS. The frequency of intact pol transcripts was highest in the motor cortex and the reverse transcriptase protein was localized to cortical neurons of ALS patients. HERV-K expression strongly correlated with TDP-43, a multi-functional protein known to be dysregulated in ALS. We have identified a specific pattern of HERV-K expression in ALS, which may potentially define the pathophysiology of ALS. Targeting of activated genome-encoded retroviral elements may open new prospects for the treatment of ALS.
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