Stable transgenic C9orf72 zebrafish model key aspects of the ALS/FTD phenotype and reveal novel pathological features.

A hexanucleotide repeat expansion (HRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is the most prevalent cause of amyotrophic lateral sclerosis/fronto-temporal dementia (ALS/FTD). Current evidence suggests HREs induce neurodegeneration through accumulation of RNA foci and/or dipeptide repeat proteins (DPR). C9orf72 patients are known to have transactive response DNA binding protein 43 kDa (TDP-43) proteinopathy, but whether there is further cross over between C9orf72 pathology and the pathology of other ALS sub-types has yet to be revealed.To address this, we generated and characterised two zebrafish lines expressing C9orf72 HREs. We also characterised pathology in human C9orf72-ALS cases. In addition, we utilised a reporter construct that expresses DsRed under the control of a heat shock promoter, to screen for potential therapeutic compounds.Both zebrafish lines showed accumulation of RNA foci and DPR. Our C9-ALS/FTD zebrafish model is the first to recapitulate the motor deficits, cognitive impairment, muscle atrophy, motor neuron loss and mortality in early adulthood observed in human C9orf72-ALS/FTD. Furthermore, we identified that in zebrafish, human cell lines and human post-mortem tissue, C9orf72 expansions activate the heat shock response (HSR). Additionally, HSR activation correlated with disease progression in our C9-ALS/FTD zebrafish model. Lastly, we identified that the compound ivermectin, as well as riluzole, reduced HSR activation in both C9-ALS/FTD and SOD1 zebrafish models.Thus, our C9-ALS/FTD zebrafish model is a stable transgenic model which recapitulates key features of human C9orf72-ALS/FTD, and represents a powerful drug-discovery tool.

Preterm birth and the timing of puberty: a systematic review.

BACKGROUND: An estimated 11% of births occur preterm, and survival is improving. Early studies suggested an association between preterm birth and earlier puberty. Given the adverse outcomes associated with early puberty this could have significant public health implications. The objective of this review was to assess the timing of puberty after preterm birth. METHODS: Pubmed, Embase, Popline, Global Health and Global Health Library were searched using terms relating to "premature birth", "menarche", "puberty" and "follow up studies". Inclusion criteria were a population consisting of pubertal or post-pubertal adolescents and adults; studies which defined preterm delivery in participants and compared outcomes to those after term delivery; and a quantitative assessment of pubertal onset. Assessment of risk of bias was conducted using principles from the Critical Appraisal Study Process. RESULTS: Our search identified 1051 studies, of which 16 met the inclusion criteria. In females, 8 studies found no association between preterm birth and the timing of menarche. Five studies found earlier onset in preterm infants, 1 found later onset, and 1 showed both earlier and later menarche, depending on birth weight. The range of effect of studies showing earlier menarche was - 0.94 to -0.07 years in the preterm group, with a median of - 0.3 years. In males, 2 studies showed earlier onset of puberty in the preterm group, 5 showed no difference, and 1 showed later onset. Most studies did not present outcomes in the form of a mean with standard deviation, precluding a meta-analysis. There was insufficient data to address potential confounding factors. CONCLUSIONS: The published evidence does not suggest that being born preterm leads to a significant acceleration in the onset of puberty. This should prove reassuring for public health purposes, and for clinicians counseling parents of infants born preterm.