Babysitting the clock

Abstract

Negative feedback is a conserved element in the maintenance of circadian rhythms. In Neurospora crassa, rhythmic oscillation is under the control of a central system in which the White Collar transcription-factor complex (WCC) stimulates expression of the clock protein FREQUENCY (FRQ). FRQ associates with the FRQ-interacting RNA helicase (FRH), and together they recruit factors that inactivate the WCC and subsequently promote the destruction of FRQ, thus resetting the cycle. Although FRH was known to stabilize FRQ and to stimulate the interaction between FRQ and the WCC, the molecular basis for FRH's activity in regulating periodicity remained poorly characterized. Dunlap and colleagues now expose an unexpected mechanism of action for FRH that is independent of its enzymatic activity and sheds light on the hitherto-underappreciated characteristics of FRQ as an intrinsically disordered protein (IDP). First, the authors demonstrated that although the helicase activity of FRH is required for normal growth, the clock function of FRH could be fully restored by a mutant devoid of helicase activity. They then showed that FRH exhibits many of the biochemical characteristics of an IDP and that its clock function probably lies in its ability to act as a 'nanny' protein to protect FRQ from premature degradation and/or spurious interactions. Although it is yet to be determined whether similar interactions are involved in regulating other circadian oscillators, the findings highlight the emerging concept that the functional properties of IDPs might often be in stabilizing interactions with cellular factors that carry distinct cellular roles. (Mol. Cell doi:10.1016/j.molcel.2013.11.005, 5 December 2013) SL Targeting huntingtin Huntington's disease (HD) is caused by the expansion of a CAG repeat within exon 1 of the huntingtin (HTT) gene, resulting in an expanded polyglutamine stretch that forms insoluble aggregates associated with neuronal dysfunction and cell death. Because transcriptional dysregulation is part of the complex pathogenesis of HD, histone deacetylases (HDACs) have been evaluated as therapeutic targets. HDAC4 is a transcriptional repressor that shuttles between the nucleus and cytoplasm and represses the transcription of genes with a role in neuronal cell death. HDAC4 is thought to self-aggregate through its glutamine-rich N terminus. Bates and colleagues now show that HDAC4 associates with mutant HTT in vivo in a polyglutamine-length– dependent manner and colocalizes with cytoplasmic inclusions in the brains of HD mouse models. HDAC4 depletion inhibited cytoplasmic aggregate formation in HD mice, and this was accompanied by a pronounced restoration of synaptic function. In addition, knockdown of HDAC4 partially restored motor coordination and other neuro-logical phenotypes and extended lifespan, thus suggesting a substantial contribution of cytoplasmic HTT aggregation to the pathology of HD. HDAC4 did not relocalize to the nucleus during disease progression, and HDAC4 knockdown had no effect on global transcriptional dysregulation and did not modulate nuclear HTT aggregation. Altogether, the data sug-gest a crucial role for cytoplasmic HTT aggregation in HD pathogenesis and identify HDAC4 as a promising therapeutic target. (PLoS Biol.