Amyotrophic lateral sclerosis (ALS) is a poorly understood neurodegenerative disease characterized predominantly by motor neuron death with no effective treatment to date. ALS has been designated as a service connected disease by VA since Veterans are at a higher risk of contracting this devastating and fatal disease. The PI of this Research Career Scientist (RCS) application, Dr. Haining Zhu, has been working on ALS for 20 years since he started his independent academic career. The long-term goal of his research program is to determine the molecular mechanisms of ALS disease pathogenesis and progression. Empowered by better mechanistic understandings, his laboratory is also engaged in translational research to discover novel therapeutic targets and to identify compounds for drug development. The success of his research program will benefit the healthcare of veterans, particularly those afflicted with ALS. Dr. Zhu's VA-funded Merit project is to study the RNA binding protein Fused in Sarcoma (FUS), which has been implicated in both familial and sporadic ALS. Familial ALS represents approximately 10-15% of all cases and ALS genes provide much-needed “molecular handles” for studying mechanisms that might be relevant to all ALS cases. His laboratory has been working on the function of FUS protein under physiological and pathological conditions. His laboratory has made several novel findings, including the identification of the nuclear localization sequence (NLS) in FUS (Gal, 2011), the determination of the crystal structure of FUS NLS in complex with the nuclear transport receptor transportin 1 (Niu, 2012), and the characterization of one of the first Drosophila models (Xia, 2012). Two of his studies were published in PNAS in 2014 and 2018, respectively. His laboratory demonstrated that liquid-liquid phase separation (LLPS) of the FUS protein played a critical role in chromatin binding and transcription regulation (Yang, 2014). His laboratory also found that FUS-positive granules contained proteins involved in protein translation and nonsense-mediated decay (NMD) of RNA. Moreover, mutant FUS suppressed protein translation and hyper-activated NMD (Kamelgarn, 2018). This work was considered so significant that PNAS published an accompanying Commentary. In the current funding period (renewed in 2020 until 2024), the overarching hypothesis is that the dysregulation of protein translation and RNA nonsense-mediated decay (NMD) contributes to FUS toxicity and motor neuron dysfunction. His laboratory proposed to determine (1) what properties of mutant FUS drive the dysregulation of protein translation and NMD; (2) whether mRNA decay and protein translation are impacted by mutant FUS with any specificity; and (3) whether corrections of these defects restore the balance between protein translation and NMD. During the proposed RCS period, Dr. Zhu plans to expand his research program by focusing on three directions. The first is to use the unique unaffected ...