Department of Biology, University of Winnipeg, 599 Portage Avenue, Winnipeg, MB R3B 2G3, Canada.
Department of Immunology, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB R3E 0T5, Canada.
Cells. 2020 Jun 30;9(7):1584. doi: 10.3390/cells9071584.
Motor neuron degeneration and spinal cord demyelination are hallmark pathological events in Amyotrophic Lateral Sclerosis (ALS). Endogenous retrovirus-K (ERVK) expression has an established association with ALS neuropathology, with murine modeling pointing to a role for the ERVK envelope () gene in disease processes. Here, we describe a novel viral protein cryptically encoded within the ERVK transcript, which resembles two distinct cysteine-rich neurotoxic proteins: conotoxin proteins found in marine snails and the Human Immunodeficiency Virus (HIV) Tat protein. Consistent with Nuclear factor-kappa B (NF-κB)-induced retrotransposon expression, the ERVK conotoxin-like protein (CTXLP) is induced by inflammatory signaling. CTXLP is found in the nucleus, impacting innate immune gene expression and NF-κB p65 activity. Using human autopsy specimens from patients with ALS, we further showcase CTXLP expression in degenerating motor cortex and spinal cord tissues, concomitant with inflammation linked pathways, including enhancement of necroptosis marker mixed lineage kinase domain-like (MLKL) protein and oligodendrocyte maturation/myelination inhibitor Nogo-A. These findings identify CTXLP as a novel ERVK protein product, which may act as an effector in ALS neuropathology.
运动神经元退化和脊髓脱髓鞘是肌萎缩侧索硬化症 (ALS) 的标志性病理事件。内源性逆转录病毒-K (ERVK) 的表达与 ALS 神经病理学有明确的关联，鼠模型表明 ERVK 包膜 () 基因在疾病过程中起作用。在这里，我们描述了一种在 ERVK 转录本中隐匿编码的新型病毒蛋白，它类似于两种不同的富含半胱氨酸的神经毒性蛋白：海洋蜗牛中的芋螺蛋白和人类免疫缺陷病毒 (HIV) Tat 蛋白。与核因子-κB (NF-κB) 诱导的反转录转座子表达一致，ERVK 芋螺蛋白样蛋白 (CTXLP) 被炎症信号诱导。CTXLP 存在于细胞核中，影响先天免疫基因表达和 NF-κB p65 活性。使用来自 ALS 患者的人体尸检标本，我们进一步展示了 CTXLP 在退化的运动皮层和脊髓组织中的表达，同时伴随着与炎症相关的途径，包括坏死性凋亡标记物混合谱系激酶结构域样 (MLKL) 蛋白和少突胶质细胞成熟/髓鞘抑制因子 Nogo-A 的增强。这些发现确定 CTXLP 为一种新型的 ERVK 蛋白产物，它可能作为 ALS 神经病理学的效应物。
