Identification of the C9ORF72 GGGGCC repeat expansion as the most common cause of ALS and FTD has generated wide interest in elucidating disease mechanisms associated with this mutation. Importantly, varied clinical manifestations and penetrance are striking characteristics of ALS associated with the C9ORF72 repeat expansion (c9ALS). Diverse neuropsychological and motor features, association with 5-7% of sporadic ALS, onset from the 4th to 8th decade and apparent nonpenetrance in obligate carriers suggest that the pathogenesis of c9ALS may differ among patients, and could be influenced by associated disease modifying genes. To elucidate the molecular basis of c9ALS and better understand its variable expression and presentation will require correlation of clinical phenotypes with effects of the repeat expansion on disease expression and potential concomitant molecular markers. Pathogenic significance of structural characteristics of the repeat expansion in relation to disease penetrance, such as repeat length and the presence of short deletions in the GC-rich sequence adjacent to the repeat is not well established. A variable loss of C9ORF72 expression in repeat carriers resulting from epigenetic changes, including trimethylation of histone H3 and H4, may also affect disease penetrance and presentation and the relationship of these molecular markers to the onset of clinical motor and neuropsychological abnormalities in c9FTD/ALS remains unknown. Alterations in C9ORF72 mRNA expression associated with aberrant histone methylation patterns in peripheral blood mononuclear cells may represent a disease-specific biomarker of toxic RNA expression and clinical features of c9FTD/ALS. In vivo biomarkers linking clinical manifestations of disease with underlying pathology could facilitate estimation of lifetime disease risk in mutation carriers, support earlier diagnosis, and provide a direct means to monitor response to therapy. However, investigation of these markers in relation to clinical phenotype, will require cross- sectional and longitudinal clinical data in c9ALS patients and asymptomatic repeat expansion carriers. As such, we hypothesize that penetrance, progression and clinical features of c9ALS may be associated with several molecular markers in peripheral blood, including the length of the C9ORF72 repeat expansion and its sequence context, tri-methylation of histone H3K9 and H3K27, expression C9ORF72 mRNA and/or TMEM106B genotype. In this Project, we propose to assess whether C9ORF72 repeat lengths (Aim 1), aberrant histone methylation (Aim 2) and C9ORF72 mRNA expression (Aim 3) respectively differ between symptomatic and asymptomatic repeat carriers, change over time in symptomatic and/or asymptomatic repeat carriers, and associate with cross-sectional and longitudinal clinical measures. Finally, we will determine whether TMEM106B is associated with the severity of cognitive changes in c9ALS patients (Aim 4).
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|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|