In this P01 resubmission proposal entitled "Pathobiology of Neurodegeneration in C9ORF72 Repeat Expansion," we seek to evaluate the mechanisms of C9ORF72 expanded repeats, the most common cause of amyotrophic lateral sclerosis (ALS) and front temporal dementia (FTD), to improve the diagnosis of and prognosis for patients suffering from c9FTD/ALS. We have assembled a world-class team combining expertise in neurology, genetics, neuropathology, and cell biology that has worked closely together and has all resources in place. Our significant progress to elucidate how expanded repeat RNA transcripts and epigenetic changes may respectively drive toxicity and haploinsufficiency in c9FTD/ALS has led to the discovery that repeat expansion size does affect disease severity, and the identification of a potential biomarker detectable in blood of c9FTD/ALS patients. We now present evidence that aberrant methylation of histone 3 at lysine 9 is detectable in brain tissue, fibroblasts and blood of C9ORF72 mutation carriers. We also identified TMEM106B as the first genetic modifier of disease phenotype in C9FTD/ALS. In drawing upon the strengths of the Mayo Clinic Neurology Department, we have begun longitudinal studies of 44 C9ALS pedigrees to determine whether expansion size, tri-methylation of histone lysine residues, mRNA expression levels and TMEM106B genotypes, correlate with phenotypic variability in c9FTD/ALS. In addition, we have since produced and characterized antibodies critical for detecting each of the five repeat-associated non-ATG (RAN) translation peptides [poly(GP), poly(GA), poly(GR), poly(PA) and poly(PR)] in cell and animal models as well as human tissue. We also provide evidence that ubiquilin-2, tau and p62/sequestosome are present in neuronal inclusions in various brain regions and spinal cord, indicating that these proteins, in addition to TDP-43, may play a role in pathogenesis of front temporal lobar degeneration with TDP-43 pathology (FTLD-TDP). We provide preliminary data that TDP-43-negative/C9RANT-positive neuronal inclusions can also be detected with antibodies to dimethylarginine, suggesting a new disease mechanism involving non-histone protein methylation. Simply put, our multi-disciplinary studies will improve understanding of C9ORF72-related neurodegeneration, identify potential biomarkers and therapeutic targets, and develop a compelling brain, biofluid and biopsy resource to aid future drug discovery.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is an incurable disease of nerve cells that control muscles. Some patients with ALS have mental and behavioral abnormalities similar to frontotemporal dementia (FTD). Researchers in this program project aim to discover the cellular disease processes initiated by mutations in the C9ORF72 gene in order to improve the diagnosis of and prognosis for patients suffering from disorders collectively referred to as c9FTD/ALS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Sutherland, Margaret L
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Mayo Clinic Jacksonville
United States
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Zhang, Yong-Jie; Jansen-West, Karen; Xu, Ya-Fei et al. (2014) Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol 128:505-24
Su, Zhaoming; Zhang, Yongjie; Gendron, Tania F et al. (2014) Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 83:1043-50