Li Wenxue, Lee Myoung-Hwa, Henderson Lisa, Tyagi Richa, Bachani Muzna, Steiner Joseph, Campanac Emilie, Hoffman Dax A, von Geldern Gloria, Johnson Kory, Maric Dragan, Morris H Douglas, Lentz Margaret, Pak Katherine, Mammen Andrew, Ostrow Lyle, Rothstein Jeffrey, Nath Avindra
Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Neurotherapeutics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Sci Transl Med. 2015 Sep 30;7(307):307ra153. doi: 10.1126/scitranslmed.aac8201.
The role of human endogenous retroviruses (HERVs) in disease pathogenesis is unclear. We show that HERV-K is activated in a subpopulation of patients with sporadic amyotrophic lateral sclerosis (ALS) and that its envelope (env) protein may contribute to neurodegeneration. The virus was expressed in cortical and spinal neurons of ALS patients, but not in neurons from control healthy individuals. Expression of HERV-K or its env protein in human neurons caused retraction and beading of neurites. Transgenic animals expressing the env gene developed progressive motor dysfunction accompanied by selective loss of volume of the motor cortex, decreased synaptic activity in pyramidal neurons, dendritic spine abnormalities, nucleolar dysfunction, and DNA damage. Injury to anterior horn cells in the spinal cord was manifested by muscle atrophy and pathological changes consistent with nerve fiber denervation and reinnervation. Expression of HERV-K was regulated by TAR (trans-activation responsive) DNA binding protein 43, which binds to the long terminal repeat region of the virus. Thus, HERV-K expression within neurons of patients with ALS may contribute to neurodegeneration and disease pathogenesis.
人类内源性逆转录病毒（HERVs）在疾病发病机制中的作用尚不清楚。我们发现，HERV-K在散发性肌萎缩侧索硬化症（ALS）患者的一个亚群中被激活，其包膜（env）蛋白可能导致神经退行性变。该病毒在ALS患者的皮质和脊髓神经元中表达，但在对照健康个体的神经元中不表达。HERV-K或其env蛋白在人类神经元中的表达导致神经突回缩和串珠样改变。表达env基因的转基因动物出现进行性运动功能障碍，伴有运动皮质体积选择性减少、锥体神经元突触活动降低、树突棘异常、核仁功能障碍和DNA损伤。脊髓前角细胞损伤表现为肌肉萎缩以及与神经纤维去神经和再支配相一致的病理变化。HERV-K的表达受TAR（反式激活应答）DNA结合蛋白43调控，该蛋白与病毒的长末端重复序列区域结合。因此，ALS患者神经元内的HERV-K表达可能导致神经退行性变和疾病发病机制。
