In this P01 proposal renewal entitled ?Pathobiology of Neurodegeneration in C9orf72 Repeat Expansion?, we seek to improve the diagnosis of and prognosis for patients suffering from C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Our integrated Projects and Cores will accomplish this by identifying therapeutic targets and biomarkers for ?c9ALS/FTD? and continuing with our productive endeavors to elucidate the mechanisms by which G4C2 repeat expansions in the C9orf72 gene cause neurodegeneration. We have assembled a world-class team of investigators with expertise in neurology, genetics, neuropathology, ?-omics?, disease modeling, biomarkers and bioinformatics that have worked closely together and have all resources in place. Our significant progress to determine the pathomechanisms underpinning c9ALS/FTD has led to the discoveries that poly(GR) proteins atypically translated from expanded G4C2 repeats correlate with neurodegeneration in c9ALS/FTD patients and cause neuronal loss in mice, and that poly(GR) induces the formation of stress granules and impairs their disassembly. The latter may account for the observed nucleocytoplasmic transport defects in c9ALS/FTD given our finding that nucleocytoplasmic transport factors are aberrantly recruited to stress granules. In the proposed projects, we will build upon these exciting findings and tackle new questions in need of answers in order to develop effective treatments for c9ALS/FTD. Indeed, deep proteomic and transcriptomic profiling, respectively, using next-generation mass spectrometry and single-nucleus RNA sequencing of brain tissues from c9ALS patients and (G4C2)149 mice will uncover protein and gene networks that represent target pathways for c9ALS. Furthermore, by interrogating the proteome and transcriptome of (G4C2)149 mice and c9ALS patient-derived neuronal cultures treated with repeat-targeting antisense oligonucleotides (ASO), we will identify protein co-expression modules and hub proteins that respond to treatment and thus represent potential therapeutic targets and candidate biomarkers. The latter represent a critical need given that the development and testing of potential ALS treatments have been seriously hampered by the lack of biomarkers to aid in the early diagnosis of ALS, to forecast disease progression, and to confirm target engagement. To enable all three research projects to effectively achieve their goals, biofluids and brain tissues from c9ALS patients will be collected by the research cores, which will also assist with analyzing and integrating data, as well as validating findings. Overall, our multi-disciplinary, synergistic studies will improve our understanding of C9orf72-related neurodegeneration, identify potential biomarkers and therapeutic targets, and develop a comprehensive brain and biofluid resource for the c9ALS field.
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