Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1

Axon loss underlies symptom onset and progression in many neurodegenerative disorders. Axon degeneration in injury and disease is promoted by activation of the nicotinamide adenine dinucleotide (NAD)-consuming enzyme SARM1. Here, we report a novel activator of SARM1, a metabolite of the pesticide and neurotoxin vacor. Removal of SARM1 completely rescues mouse neurons from vacor-induced neuron and axon death in vitro and in vivo. We present the crystal structure the Drosophila SARM1 regulatory domain complexed with this activator, the vacor metabolite VMN, which as the most potent activator yet know is likely to support drug development for human SARM1 and NMNAT2 disorders. This study indicates the mechanism of neurotoxicity and pesticide action by vacor, raises important questions about other pyridines in wider use today, provides important new tools for drug discovery, and demonstrates that removing SARM1 can robustly block programmed axon death induced by toxicity as well as genetic mutation

Analyses of genome architecture and gene expression reveal novel candidate virulence factors in the secretome of Phytophthora infestans

<p>Abstract</p> <p>Background</p> <p><it>Phytophthora infestans </it>is the most devastating pathogen of potato and a model organism for the oomycetes. It exhibits high evolutionary potential and rapidly adapts to host plants. The <it>P. infestans </it>genome experienced a repeat-driven expansion relative to the genomes of <it>Phytophthora sojae </it>and <it>Phytophthora ramorum </it>and shows a discontinuous distribution of gene density. Effector genes, such as members of the RXLR and Crinkler (CRN) families, localize to expanded, repeat-rich and gene-sparse regions of the genome. This distinct genomic environment is thought to contribute to genome plasticity and host adaptation.</p> <p>Results</p> <p>We used <it>in silico </it>approaches to predict and describe the repertoire of <it>P. infestans </it>secreted proteins (the secretome). We defined the "plastic secretome" as a subset of the genome that (i) encodes predicted secreted proteins, (ii) is excluded from genome segments orthologous to the <it>P. sojae </it>and <it>P. ramorum </it>genomes and (iii) is encoded by genes residing in gene sparse regions of <it>P. infestans </it>genome. Although including only ~3% <it>of P. infestans </it>genes, the plastic secretome contains ~62% of known effector genes and shows >2 fold enrichment in genes induced <it>in planta</it>. We highlight 19 plastic secretome genes induced <it>in planta </it>but distinct from previously described effectors. This list includes a trypsin-like serine protease, secreted oxidoreductases, small cysteine-rich proteins and repeat containing proteins that we propose to be novel candidate virulence factors.</p> <p>Conclusions</p> <p>This work revealed a remarkably diverse plastic secretome. It illustrates the value of combining genome architecture with comparative genomics to identify novel candidate virulence factors from pathogen genomes.</p

A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration.

NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN-scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein Wld(S) prevent this rise. These data indicate that the mechanism by which NMNAT and the related Wld(S) protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies

Rapporti tra tipi vegetazionali e substrato roccioso nell’area umbro-marchigiana.

In this area, Ostrya carpinifolia woods with Quercus cerris are related to the diffusion of "calcari diasprini". Quercus pubescens woods almost exclusively pertain to ares covered by nappe detritus and calcareous-marly detritus; woody communities of Quercus cerris are explained by the presence of fersiallitic paleosols

Sulla distribuzione dei paleosuoli fersiallitici e dei boschi a Quercus cerris L. nel territorio del Foglio n. 324 (Foligno).

Lo studio mette in evidenza lo stretto rapporto tra substrato roccioso e copertura vegetale. Attraverso cartografie dettagliate vengono messe in evidenza le variazioni composizionali all'interno delle formazioni rocciose, la composizione particolare di coperture continentali e i particolari contesti dell'evoluzione geomorfologica, passa e in atto

The vascular flora of the Altipiani di Colfiorito (Umbria-Marches Apennines, Italy)

The Altipiani di Colfiorito are a system of seven tectonic depressions with karstic phenomena, located in the Umbria-Marches Apennine ridge (Italy). This area is characterized by the presence of wetlands which have been internationally protected through the institution of a Ramsar Site, an Important Bird Area, three Sites of Community Importance and a Special Protection Area. The analysis of bibliographic and herbarium data and the floristic field research carried out from 1999 to 2008, allowed to list 657 floristic units, belonging to 88 families and 320 genera. Among them, 11 (Avena sativa subsp. macrantha, A. sterilis subsp. ludoviciana, Chenopodium hybridum, Cuscuta campestris, Mentha arvensis, Rosa andegavensis, R. dumalis, Schedonorus uechtritzianus, Scrophularia umbrosa, Trifolium alexandrinum and Veronica catenata) are new for the Umbrian flora and 2 (Crypsis alopecuroides and Schedonorus uechtritzianus) for the Marchean flora. Numerous rare and threatened species in Umbrian and Marchean flora, such as Alopecurus bulbosus, Carex tomentosa, Equisetum fluviatile, Juncus hybridus, Nymphaea alba, Ophioglossum vulgatum, Ranunculus flammula, R. ophioglossifolius, Trifolium patens and Utricularia australis, have been found. Nevertheless some species, previously recorded for Palude di Colfiorito, such as Eriophorum latifolium, Hippuris vulgaris, Hydrocotyle vulgaris, Menyanthes trifoliata, Potamogeton lucens, P. trichoides, Ranunculus lingua and Triglochin palustre, were not found and considered locally extinct