Amyloid-β (Aβ) peptides, derived from the amyloid precursor protein, and the microtubuleassociated protein tau are key pathogenic factors in Alzheimer's disease (AD). How exactly they impair cognitive functions is unknown. Here we assessed the effects of Aβ and tau on axonal transport of mitochondria and the neurotrophin receptor TrkA, cargoes that are critical for neuronal function and survival and whose distributions are altered in AD. Aβ oligomers rapidly inhibited axonal transport of these cargoes in wildtype neurons. Lowering tau levels prevented these defects without affecting baseline axonal transport. Thus, Aβ requires tau to impair axonal transport and tau reduction protects against Aβ-induced axonal transport defects.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded stretch of CAG trinucleotide repeats that results in neuronal dysfunction and death. Here, the HD consortium reports the generation and characterization of 14 induced pluripotent stem cell (iPSC) lines from HD patients and controls. Microarray profiling revealed CAG expansion-associated gene expression patterns that distinguish patient lines from controls, and early onset versus late onset HD. Differentiated HD neural cells showed disease associated changes in electrophysiology, metabolism, cell adhesion, and ultimately cell death for lines with both medium and longer CAG repeat expansions. The longer repeat lines were however the most vulnerable to cellular stressors and BDNF withdrawal using a range of assays across consortium laboratories. The HD iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in HD and provides a novel human stem cell platform for screening new candidate therapeutics.

We describe a collection of P-element insertions that have considerable utility for generating custom chromosomal aberrations in Drosophila melanogaster. We have mobilized a pair of engineered P elements, p{RS3} and p{RS5}, to collect 3243 lines unambiguously mapped to the Drosophila genome sequence. The collection contains, on average, an element every 35 kb. We demonstrate the utility of the collection for generating custom chromosomal deletions that have their end points mapped, with base-pair resolution, to the genome sequence. The collection was generated in an isogenic strain, thus affording a uniform background for screens where sensitivity to genetic background is high. The entire collection, along with a computational and genetic toolbox for designing and generating custom deletions, is publicly available. Using the collection it is theoretically possible to generate Ͼ12,000 deletions between 1 bp and 1 Mb in size by simple eye color selection. In addition, a further 37,000 deletions, selectable by molecular screening, may be generated. We are now using the collection to generate a second-generation deficiency kit that is precisely mapped to the genome sequence. G ENETICALLY tractable model organisms are valufor components that function in particular pathways and characterize how individual genes participate in able research tools for uncovering basic biological such pathways. principles that are conserved through evolution. ManyThe fruit fly, Drosophila melanogaster, is one such tractamolecular pathways, such as signaling cascades, gene ble model that has been used extensively to elucidate regulatory pathways, and cell cycle control circuits, were many conserved genetic hierarchies. One particularly first characterized genetically in model systems. The powerful approach with Drosophila is the ability to rapsubsequent molecular cloning of the genes involved in idly carry out focused genome-wide screens for pathsuch pathways has shown how evolution has utilized way components by identifying loci that modify specific basic molecular building blocks to control a wide variety phenotypes (see St. Johnston 2002 for review). In this of biological processes. Key to the success of such apapproach, a sensitized genetic background, most comproaches has been the ability to carry out genetic screens monly exhibiting an easily scored adult phenotype such as rough eyes or a wing defect, is used to search for mutations in genes that make the phenotype more se- sensitized background and the phenotype is assessed. specific recombinase (FRT site) placed within intron one. In the case of RS3, a second FRT site is placed Importantly, the mutagenized chromosome is heterozygous, allowing genetic interactions between the sensiupstream of the first of the mini-white exons; in the case of RS5 the second FRT site is located downstream of tized background and mutations that are homozygous lethal to be detected. Particularly useful tools for such the mini-white exons. Golic and Golic demonstrated how a pair of RS3 and RS5 e...

In polyglutamine (polyQ) diseases, only certain neurons die, despite widespread expression of the offending protein. PolyQ expansion may induce neurodegeneration by impairing proteostasis, but protein aggregation and toxicity tend to confound conventional measurements of protein stability. Here, we used optical pulse labeling to measure effects of polyQ expansions on the mean lifetime of a fragment of huntingtin, the protein that causes Huntington's disease, in living neurons. We show that polyQ expansion reduced the mean lifetime of mutant huntingtin within a given neuron and that the mean lifetime varied among neurons, indicating differences in their capacity to clear the polypeptide. We found that neuronal longevity is predicted by the mean lifetime of huntingtin, as cortical neurons cleared mutant huntingtin faster and lived longer than striatal neurons. Thus, cell type–specific differences in turnover capacity may contribute to cellular susceptibility to toxic proteins, and efforts to bolster proteostasis in Huntington's disease, such as protein clearance, could be neuroprotective.