Grants and Contracts Details


Frontotemporal dementia (FTD) is an age-related non-Alzheimer dementia characterized by progressive neuronal loss in the frontotemporal lobes. A subset of FTD is defined by the pathology of protein inclusions positive for Fused in Sarcoma (FUS), thus named FUS-FTD. FTD and amyotrophic lateral sclerosis (ALS) share a wide spectrum of clinical, pathological and genetic features. Pathogenic mutations of FUS cause both ALS and FTD, and FUS proteinopathy is also detected in sporadic diseases. FUS is primarily in the nucleus, but the protein with a disease-causing mutation mislocalizes and accumulates in the cytoplasm. Protein aggregates induced by FUS mutations may sequester other proteins to compromise cellular functions, resulting in impaired neurons. We recently showed that FTD/ALS mutations of FUS suppressed protein translation and hyperactivated the nonsense-mediated decay (NMD) of mRNAs. The hypothesis to be tested in this project is that the dysregulation of protein translation and mRNA surveillance contributes to cortical neuron loss in FUS-FTD. Three specific aims are designed to test the hypothesis using in vitro and animal models as well as FTD patient tissues. Aim 1 is to determine how mRNA NMD and protein translation are perturbed by pathogeneic FUS mutations in FTD mouse models and patient tissues. We will determine whether NMD factors and translationrelated proteins are sequestered in FUS inclusions in forebrain neurons in R521G FUS transgenic mice at different ages. We will measure mRNA turnover rates and protein translation efficiency in R521G FUS mice and correlate the perturbations to neuronal dysfunction and FTD disease progression. Moreover, we will examine whether NMD factors and protein translation proteins are sequestered in FTD patient tissues. Aim 2 is to identify specific proteins suppressed by pathogenic FUS in FTD mice. We will apply the puromycin labeling in FTD mice and use the proteomic approach to identify changes in protein translation impacted by mutant FUS in forebrain neurons. In addition, actively translated mRNAs will be identified and quantified in polysome fractions using RNASeq. Results from the –omics approaches will be integrated for pathway analysis to reveal whether pathogenic FUS impairs proteins in specific pathways, providing novel insights into the FTD etiology. Aim 3 is to elucidate the significance of RNA binding and post-translational modifications in the dysfunction of pathogenic FUS. We will use a cohort of RNA binding-deficient mutations in an optogenetic Cry2olig-FUS-mCherry system to examine the significance of RNA binding in FUS inclusion formation and dysfunction in cortical neurons. We recently found FUS is acetylated at residues critical to RNA binding, we will test how acetylation-null and -mimicking mutations affect FUS inclusions, NMD and protein translation. In addition, we will also examine whether pathogenic FUS forms RNA-dependent and -independent inclusions that produce different levels of toxicity to neurons. The proposed experiments will thoroughly examine a novel disease mechanism using innovative approaches. Completion of our proposed work will help elucidate molecular mechanisms underlying FUS FTD.
Effective start/end date8/15/206/30/21


  • National Institute of Neurological Disorders & Stroke: $536,706.00


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