The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

Fig. 2.Transformants releasing E␤C suffered less damage than control lines when EPNs were present. (A) Root damage measured on plants that had received neither WCR eggs nor nematodes was minimal, and there was no difference between transformed and nontransformed plants (n ϭ 5, P ϭ 0.87). (B) Root damage on plants that received only WCR eggs, but no nematodes, was substantial. Again, no significant difference was found between the transformed and nontransformed plants (n ϭ 5, P ϭ 0.18). (C) In plots that received WCR eggs and H. megidis, roots from transformed plants (pooled) had significantly less damage than roots from control lines (n ϭ 30, P ϭ 0.007). Approximately one-quarter of the transformed plants were found not to emit E␤C. Removing these plants from the statistical analysis did not significantly affect the results. The letters above the bars indicate significant differences within a graph. Error bars indicate standard errors.

Autophagy is the principal cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Recently, autophagy has been implicated in neurodegeneration, but whether it is detrimental or protective remains unclear. Here we report that beclin 1, a protein with a key role in autophagy, was decreased in affected brain regions of patients with Alzheimer disease (AD) early in the disease process. Heterozygous deletion of beclin 1 (Becn1) in mice decreased neuronal autophagy and resulted in neurodegeneration and disruption of lysosomes. In transgenic mice that express human amyloid precursor protein (APP), a model for AD, genetic reduction of Becn1 expression increased intraneuronal amyloid β (Aβ) accumulation, extracellular Aβ deposition, and neurodegeneration and caused microglial changes and profound neuronal ultrastructural abnormalities. Administration of a lentiviral vector expressing beclin 1 reduced both intracellular and extracellular amyloid pathology in APP transgenic mice. We conclude that beclin 1 deficiency disrupts neuronal autophagy, modulates APP metabolism, and promotes neurodegeneration in mice and that increasing beclin 1 levels may have therapeutic potential in AD. IntroductionFamilial Alzheimer disease (AD) mutations increase the toxicity and amyloidogenicity of the amyloid β (Aβ) peptide, placing disruption of amyloid precursor protein (APP) metabolism and Aβ production at the center of AD pathogenesis (1). However, less than 2% of AD cases are caused by autosomal-dominant mutations. Familial AD caused by these mutations and the remaining nondominant sporadic AD cases are pathologically similar. Therefore, factors that disrupt APP metabolism and Aβ production, such as increased APP transcription, increased production of amyloidogenic Aβ (2), and decreased APP degradation, may contribute to the pathogenesis of sporadic AD as well.The etiology of AD is distinct from that of other neurodegenerative diseases, such as Parkinson disease and Huntington disease (HD), but all are characterized pathologically by the presence of abnormal protein aggregates and neuronal death (3, 4). Protein aggregates may form by abnormal folding or proteolytic processing of proteins or by the disturbance of intracellular protein degradation pathways (3,5). Autophagy is involved in the intracellular degradation of aggregation-prone α-synuclein (6) and huntingtin

Accumulation of unwanted/misfolded proteins in aggregates has been observed in airways of patients with cystic fibrosis (CF), a life-threatening genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Here we show how the defective CFTR results in defective autophagy and decreases the clearance of aggresomes. Defective CFTR-induced upregulation of reactive oxygen species (ROS) and tissue transglutaminase (TG2) drive the crosslinking of beclin 1, leading to sequestration of phosphatidylinositol-3-kinase (PI(3)K) complex III and accumulation of p62, which regulates aggresome formation. Both CFTR knockdown and the overexpression of green fluorescent protein (GFP)-tagged-CFTR(F508del) induce beclin 1 downregulation and defective autophagy in non-CF airway epithelia through the ROS-TG2 pathway. Restoration of beclin 1 and autophagy by either beclin 1 overexpression, cystamine or antioxidants rescues the localization of the beclin 1 interactome to the endoplasmic reticulum and reverts the CF airway phenotype in vitro, in vivo in Scnn1b-transgenic and Cftr(F508del) homozygous mice, and in human CF nasal biopsies. Restoring beclin 1 or knocking down p62 rescued the trafficking of CFTR(F508del) to the cell surface. These data link the CFTR defect to autophagy deficiency, leading to the accumulation of protein aggregates and to lung inflammation.

Accumulation of the synaptic protein ␣-synuclein (␣-syn) is a hallmark of Parkinson's disease (PD) and Lewy body disease (LBD),