Rex Cody, Nadeau Marie-Josée, Douville Renée, Schellenberg Kerri
Department of Biology, University of Winnipeg, Winnipeg, MB, Canada.
Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.
Front Neurol. 2019 Sep 4;10:968. doi: 10.3389/fneur.2019.00968. eCollection 2019.
Spinal and Bulbar Muscular Atrophy (SBMA) is caused by the extension of the polyglutamine tract within the androgen receptor (AR) gene, and results in a multisystem presentation, including the degeneration of lower motor neurons. The androgen receptor (AR) is known to modulate the expression of endogenous retrovirus-K (ERVK), a pathogenic viral genomic symbiont. Since ERVK is associated with motor neuron disease, such as Amyotrophic Lateral Sclerosis (ALS), we sought to determine if patients with SBMA exhibit evidence of ERVK reactivation. Data from a pilot study demonstrate that peripheral blood mononuclear cell (PBMC) samples from controls and patients with SBMA were examined for the expression of ERVK viral transcripts and proteins. No differences in ERVK RNA expression was observed between the clinical groups. In contrast, enhancement of processed ERVK Gag and integrase proteins were observed in SBMA-derived PBMC as compared to healthy control specimens. Increased ERVK protein maturation co-occurred with elevation in the expression of the pro-inflammatory transcription factor IRF1 in SBMA. Our findings indicate that ERVK viral protein maturation in SBMA is an unrecognized biomarker and facet of the disease. We discuss how our current understanding of ERVK-driven pathology may tie into key aspects of multi-system dysfunction in SBMA, with a focus on inflammation, proteinopathy, as well as DNA damage and repair.
脊髓延髓性肌萎缩症（SBMA）由雄激素受体（AR）基因内多聚谷氨酰胺序列的延长所致，会导致多系统症状，包括下运动神经元变性。已知雄激素受体（AR）可调节内源性逆转录病毒K（ERVK，一种致病性病毒基因组共生体）的表达。由于ERVK与运动神经元疾病相关，如肌萎缩侧索硬化症（ALS），我们试图确定SBMA患者是否有ERVK重新激活的证据。一项初步研究的数据表明，对对照组和SBMA患者的外周血单个核细胞（PBMC）样本进行了ERVK病毒转录本和蛋白质表达检测。临床组之间未观察到ERVK RNA表达的差异。相比之下，与健康对照样本相比，在源自SBMA的PBMC中观察到加工后的ERVK Gag和整合酶蛋白有所增强。SBMA中ERVK蛋白成熟增加与促炎转录因子IRF1表达升高同时出现。我们的研究结果表明，SBMA中ERVK病毒蛋白成熟是一种未被认识的生物标志物和该疾病的一个方面。我们讨论了我们目前对ERVK驱动的病理学的理解如何与SBMA多系统功能障碍的关键方面相关联，重点是炎症、蛋白病以及DNA损伤和修复。
