Jackson Kasey L, Dhaibar Hemangini A, Dayton Robert D, Cananzi Sergio G, Mayhan William G, Glasscock Edward, Klein Ronald L
Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA, 71130, USA.
Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA, 71130, USA.
BMC Neurosci. 2016 Oct 28;17(1):69. doi: 10.1186/s12868-016-0304-5.
Fused in sarcoma (FUS) is an RNA-binding protein associated with the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. ALS manifests in patients as a progressive paralysis which leads to respiratory dysfunction and failure, the primary cause of death in ALS. We expressed human FUS in rats to determine if FUS would induce ALS relevant respiratory changes to serve as an early stage disease indicator. The FUS expression was initiated in adult rats by way of an intravenously administered adeno-associated virus vector serotype 9 (AAV9) providing an adult onset model.
The rats developed progressive motor impairments observed as early as 2-3 weeks post gene transfer. Respiratory abnormalities manifested 4-7 weeks post gene transfer including increased respiratory frequency and decreased tidal volume. Rats with breathing abnormalities also had arterial blood acidosis. Similar detailed plethysmographic changes were found in adult rats injected with AAV9 TDP-43. FUS gene transfer to adult rats yielded a consistent pre-clinical model with relevant motor paralysis in the early to middle stages and respiratory dysfunction at the end stage. Both FUS and TDP-43 yielded a similar consistent disease state.
This modeling method yields disease relevant motor and respiratory changes in adult rats. The reproducibility of the data supports the use of this method to study other disease related genes and their combinations as well as a platform for disease modifying interventional strategies.
肉瘤融合蛋白（FUS）是一种与神经退行性疾病肌萎缩侧索硬化症（ALS）和额颞叶痴呆相关的RNA结合蛋白。ALS患者表现为进行性瘫痪，最终导致呼吸功能障碍和衰竭，这是ALS患者的主要死因。我们在大鼠中表达人FUS，以确定FUS是否会引发与ALS相关的呼吸变化，作为疾病早期指标。通过静脉注射9型腺相关病毒载体（AAV9）在成年大鼠中启动FUS表达，从而建立成年发病模型。
在基因转移后2 - 3周即可观察到大鼠出现进行性运动障碍。呼吸异常出现在基因转移后4 - 7周，包括呼吸频率增加和潮气量减少。有呼吸异常的大鼠还出现动脉血酸中毒。在注射AAV9 TDP - 43的成年大鼠中也发现了类似的详细体积描记变化。将FUS基因转移到成年大鼠中产生了一个一致的临床前模型，在早期至中期出现相关运动麻痹，在末期出现呼吸功能障碍。FUS和TDP - 43都产生了相似的一致疾病状态。
这种建模方法在成年大鼠中产生了与疾病相关的运动和呼吸变化。数据的可重复性支持使用该方法研究其他疾病相关基因及其组合，以及作为疾病修饰干预策略的平台。
