Huntingtin Interacting Proteins Are Genetic Modifiers of Neurodegeneration

Huntington's disease (HD) is a fatal neurodegenerative condition caused by expansion of the polyglutamine tract in the huntingtin (Htt) protein. Neuronal toxicity in HD is thought to be, at least in part, a consequence of protein interactions involving mutant Htt. We therefore hypothesized that genetic modifiers of HD neurodegeneration should be enriched among Htt protein interactors. To test this idea, we identified a comprehensive set of Htt interactors using two complementary approaches: high-throughput yeast two-hybrid screening and affinity pull down followed by mass spectrometry. This effort led to the identification of 234 high-confidence Htt-associated proteins, 104 of which were found with the yeast method and 130 with the pull downs. We then tested an arbitrary set of 60 genes encoding interacting proteins for their ability to behave as genetic modifiers of neurodegeneration in a Drosophila model of HD. This high-content validation assay showed that 27 of 60 orthologs tested were high-confidence genetic modifiers, as modification was observed with more than one allele. The 45% hit rate for genetic modifiers seen among the interactors is an order of magnitude higher than the 1%–4% typically observed in unbiased genetic screens. Genetic modifiers were similarly represented among proteins discovered using yeast two-hybrid and pull-down/mass spectrometry methods, supporting the notion that these complementary technologies are equally useful in identifying biologically relevant proteins. Interacting proteins confirmed as modifiers of the neurodegeneration phenotype represent a diverse array of biological functions, including synaptic transmission, cytoskeletal organization, signal transduction, and transcription. Among the modifiers were 17 loss-of-function suppressors of neurodegeneration, which can be considered potential targets for therapeutic intervention. Finally, we show that seven interacting proteins from among 11 tested were able to co-immunoprecipitate with full-length Htt from mouse brain. These studies demonstrate that high-throughput screening for protein interactions combined with genetic validation in a model organism is a powerful approach for identifying novel candidate modifiers of polyglutamine toxicity

Observations Of Type Ia Supernova 2014J With Flitecam On SOFIA

We present medium-resolution near-infrared (NIR) spectra, covering 1.1-3.4 mu m, of the normal Type Ia supernova (SN Ia) SN 2014J in M82 obtained with the FLITECAM instrument on board Stratospheric Observatory for Infrared Astronomy (SOFIA) between 17 and 26 days after maximum B light. Our 2.8-3.4 mu m spectra may be the first similar to 3 mu m spectra of an SN Ia ever published. The spectra spanning the 1.5-2.7 mu m range are characterized by a strong emission feature at similar to 1.77 mu m with a FWHM of similar to 11,000-13,000 kms(-1). We compare the observed FLITECAM spectra to the recent non-LTE delayed detonation models of Dessart et al. and find that the models agree with the spectra remarkably well in the 1.5-2.7 mu m wavelength range. Based on this comparison we identify the similar to 1.77 mu m emission peak as a blend of permitted lines of Co II. Other features seen in the 2.0-2.5 mu m spectra are also identified as emission from permitted transitions of Co II. However, the models are not as successful at reproducing the spectra in the 1.1-1.4 mu m range or between 2.8 and 3.4 mu m. These observations demonstrate the promise of SOFIA, which allows access to wavelength regions inaccessible from the ground, and serve to draw attention to the usefulness of the regions between the standard ground-based NIR passbands for constraining SN models.NSFNASA NAS2-97001Deutsches SOFIA Institut (DSI) under DLR 50 OK 0901SOFIA Cycle 2 GI Research Grant 75-0001, 75-0002, 02-0100NASA through USRA 08500-05Astronom

Per una filosofia del limite: Sergio Cotta interprete di Montesquieu

Scritti in memoria di Sergio Cott