CLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegeneration

SummaryNeurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

DNA-PK promotes the survival of young neurons in the embryonic mouse retina.

Supplementary Information accompanies the paper on Cell Death and Differentiation website: http://www.nature.com/cdd/journal/v17/n11/suppinfo/cdd201046s1.htmlProgrammed cell death is a crucial process in neural development that affects mature neurons and glial cells, as well as proliferating precursors and recently born neurons at earlier stages. However, the regulation of the early phase of neural cell death and its function remain relatively poorly understood. In mouse models defective in homologous recombination or nonhomologous end-joining (NHEJ), which are both DNA double-strand break (DSB) repair pathways, there is massive cell death during neural development, even leading to embryonic lethality. These observations suggest that natural DSBs occur frequently in the developing nervous system. In this study, we have found that several components of DSB repair pathways are activated in the developing mouse retina at stages that coincide with the onset of neurogenesis. In short-term organotypic retinal cultures, we confirmed that the repair pathways can be modulated pharmacologically. Indeed, inhibiting the DNA-dependent protein kinase (DNA-PK) catalytic subunit, which is involved in NHEJ, with NU7026 increased caspase-dependent cell death and selectively reduced the neuron population. This observation concurs with an increase in the number of apoptotic neurons found after NU7026 treatment, as also observed in the embryonic scid mouse retina, a mutant that lacks DNA-PK catalytic subunit activity. Therefore, our results implicate the generation of DSB and DNA-PK-mediated repair in neurogenesis in the developing retina.This work was supported by the Ministerio de Ciencia e Innovación, Spain (Grant SAF2007–66175 to EJdlR). JB is an FPI Fellow (Ministerio de Ciencia e Innovación).Peer reviewe