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

A High-Yielding Synthesis of the Naturally Occurring Antitumour Agent Irisquinone

A short, high-yielding synthesis of the antitumour agent irisquinone (1) is described. The key steps are the palladium catalysed coupling reaction of dec-9-yn-1-ol with iodide (2) to form alkyne (3) and the Fremy’s salt oxidation of phenol (7)

A convenient synthesis of the paclitaxel side-chain via a diastereoselective Staudinger reaction

The N-benzylidene dexivative of (S)-(-)-1-(p-mathoxyphenyl)propyl-1- amine, obtained by a new resolution procedure, exhibits moderate selectivity in the reaction with 2-acetoxyketene; the (S)-(-)-1-(p-methoxyphenyl)propyl group can be oxidatively cleaved from the resultant β-lactam, an important precursor for taxane semi-synthesis.</p

CCDC 184591: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 184589: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures