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.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is an incurable disease of nerve cells that control muscles. Some patients with ALS have cognitive and behavioral abnormalities similar to frontotemporal dementia (FTD). Researchers in this program project aim to discover the cellular processes initiated by a mutation in the C9orf72 gene in order to improve the diagnosis of and prognosis for patients suffering from disorders collectively referred to as c9ALS/FTD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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Special Emphasis Panel (ZNS1)
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Gubitz, Amelie
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Mayo Clinic Jacksonville
United States
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Eftekharzadeh, Bahareh; Daigle, J Gavin; Kapinos, Larisa E et al. (2018) Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease. Neuron 99:925-940.e7
Nicolas, Aude (see original citation for additional authors) (2018) Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron 97:1268-1283.e6
Nicholson, Alexandra M; Zhou, Xiaolai; Perkerson, Ralph B et al. (2018) Loss of Tmem106b is unable to ameliorate frontotemporal dementia-like phenotypes in an AAV mouse model of C9ORF72-repeat induced toxicity. Acta Neuropathol Commun 6:42
Kang, Silvia S; Ebbert, Mark T W; Baker, Kelsey E et al. (2018) Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau. J Exp Med 215:2235-2245
Gendron, Tania F; Petrucelli, Leonard (2018) Disease Mechanisms of C9ORF72 Repeat Expansions. Cold Spring Harb Perspect Med 8:
Ebbert, Mark T W; Farrugia, Stefan L; Sens, Jonathon P et al. (2018) Long-read sequencing across the C9orf72 'GGGGCC' repeat expansion: implications for clinical use and genetic discovery efforts in human disease. Mol Neurodegener 13:46
Wang, Zi-Fu; Ursu, Andrei; Childs-Disney, Jessica L et al. (2018) The Hairpin Form of r(G4C2)exp in c9ALS/FTD Is Repeat-Associated Non-ATG Translated and a Target for Bioactive Small Molecules. Cell Chem Biol :
Sakae, Nobutaka; Bieniek, Kevin F; Zhang, Yong-Jie et al. (2018) Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease. Acta Neuropathol Commun 6:63
Mordes, Daniel A; Prudencio, Mercedes; Goodman, Lindsey D et al. (2018) Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients. Acta Neuropathol Commun 6:55
Pottier, Cyril; Zhou, Xiaolai; Perkerson 3rd, Ralph B et al. (2018) Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Lancet Neurol 17:548-558

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