FUS-NLS mutation causes neurodevelopmental and systemic metabolic alterations

Mutations in the ubiquitously expressed DNA/RNA binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). While most FUS mutation studies have focused on motor neuron degeneration, little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues given the link between ALS-FTD and altered metabolism. To investigate pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity 6 tissues (frontal cortex, spinal cord, tibialis anterior, liver, iWAT and BAT) from wild type and Fus delta14/delta14 male mice at 9.5 weeks of age (n=4)广泛表达的DNA/RNA结合蛋白FUS的突变，可引发侵袭性青少年型肌萎缩侧索硬化症（amyotrophic lateral sclerosis, ALS）。尽管多数FUS突变相关研究聚焦于运动神经元变性，但学界对其更广泛的全身性或发育层面影响仍知之甚少。本研究针对携带纯合致病性FUSDelta14突变的生理性敲入小鼠模型，探究其多效性表型。我们对多个器官开展RNA测序（RNA sequencing），旨在鉴定突变蛋白在全身性转录组中改变的通路；鉴于ALS-FTD与代谢异常存在关联，研究同时纳入了代谢组织相关分析。为探究上述纯合致病性FUSDelta14突变生理性敲入小鼠的多效性表型，本研究采集了9.5周龄野生型与Fus delta14/delta14雄性小鼠的6种组织：额叶皮层（frontal cortex）、脊髓（spinal cord）、胫前肌（tibialis anterior）、肝脏、腹股沟白色脂肪组织（inguinal white adipose tissue, iWAT）以及棕色脂肪组织（brown adipose tissue, BAT），每组样本量为4（n=4）。