The recent development of imaging-based biomarkers that track the progression of tau pathology in living patients should greatly facilitate the early phase testing of tau immunotherapies and other tau-targeting therapeutics (Maruyama et al., 2013). “
“Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative disorders

that share overlapping pathologies, genetic causes, and a lack of disease-modifying PI3K inhibitor treatments (Ling et al., 2013). Precisely two years ago, adjoining papers in Neuron identified large intronic GGGGCC repeat expansions in a gene of unknown function, C9orf72, as a common genetic cause of both FTD and ALS (C9FTD/ALS) ( Renton et al., 2011 and DeJesus-Hernandez et al., 2011). The discovery sparked great interest selleck chemical in the field, partly because the C9orf72 expansion looked a lot like something scientists had seen before: the CUG and CCUG repeats that cause the common dominantly inherited muscle disease myotonic

dystrophy (DM). Work over the past 20 years has demonstrated that repeat expansions in two genes, a CUG repeat in DMPK (in DM1) and a CCUG repeat in ZF9 (in DM2), elicit dominantly inherited disease through a “toxic RNA” gain-of-function mechanism: as RNA, the expanded repeats bind to splicing factors, inhibiting their normal functions. In DM1, for example, the expanded CUG repeat binds Muscleblind-Like

(MBNL) RNA binding proteins, sequestering them in nuclear foci and causing abnormal splicing of key transcripts in muscle and brain. Sodium butyrate Mice lacking MBNL1 or MBNL2 recapitulate disease features of DM1, and conversely, boosting MBNL protein expression suppresses CUG repeat-associated toxicity in model systems (reviewed in Lee and Cooper, 2009). These findings laid the groundwork for successful preclinical trials using antisense oligonucleotides (ASOs) to eliminate the toxic CUG repeat RNA in mouse models ( Wheeler et al., 2012), with plans for a follow-up clinical trial in DM1 patients soon. By contrast, how the GGGGCC repeat expansion triggers C9FTD/ALS is less clear for at least three reasons. First, the case for RNA toxicity in C9FTD/ALS is incomplete. Although GGGGCC RNA foci are present in disease tissues, it remains uncertain whether proteins are bound by the RNA repeat to a degree that would impair normal functions. Experiments that rescue disease features by overexpressing specific sequestered proteins or recapitulate disease features by knocking down the same sequestered proteins have not been reported. Second, expression of C9orf72 mRNA in C9FTD/ALS patients is reduced by ∼50% (DeJesus-Hernandez et al., 2011 and Gijselinck et al., 2012) and the expanded repeat and neighboring CpG islands are hypermethylated (Xi et al.