Reducing insulin/IGF signaling allows for organismal survival during periods of inhospitable conditions by regulating the diapause state, whereby the organism stockpiles lipids, reduces fertility, increases stress resistance, and has an increased lifespan. The Target of Rapamycin (TOR) responds to changes in growth factors, amino acids, oxygen tension, and energy status; however, it is unclear how TOR contributes to physiological homeostasis and disease conditions. Here, we show that reducing the function of Drosophila TOR results in decreased lipid stores and glucose levels. Importantly, this reduction of dTOR activity blocks the insulin resistance and metabolic syndrome phenotypes associated with increased activity of the insulin responsive transcription factor, dFOXO. Reduction in dTOR function also protects against age-dependent decline in heart function and increases longevity. Thus, the regulation of dTOR activity may be an ancient "systems biological" means of regulating metabolism and senescence, that has important evolutionary, physiological, and clinical implications.

Parkinson disease is caused by the death of midbrain dopamine neurons from oxidative stress, abnormal protein aggregation, and genetic predisposition. In 2003, Bonifati et al. (23) found that a single amino acid mutation in the DJ-1 protein was associated with early-onset, autosomal recessive Parkinson disease (PARK7). The mutation L166P prevents dimerization that is essential for the antioxidant and gene regulatory activity of the DJ-1 protein. Because low levels of DJ-1 cause Parkinson, we reasoned that overexpression might stop the disease. We found that overexpression of DJ-1 improved tolerance to oxidative stress by selectively up-regulating the rate-limiting step in glutathione synthesis. When we imposed a different metabolic insult, A53T mutant ␣-synuclein, we found that DJ-1 turned on production of the chaperone protein Hsp-70 without affecting glutathione synthesis. After screening a number of small molecules, we have found that the histone deacetylase inhibitor phenylbutyrate increases DJ-1 expression by 300% in the N27 dopamine cell line and rescues cells from oxidative stress and mutant ␣-synuclein toxicity. In mice, phenylbutyrate treatment leads to a 260% increase in brain DJ-1 levels and protects dopamine neurons against 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) toxicity. In a transgenic mouse model of diffuse Lewy body disease, long-term administration of phenylbutyrate reduces ␣-synuclein aggregation in brain and prevents age-related deterioration in motor and cognitive function. We conclude that drugs that up-regulate DJ-1 gene expression may slow the progression of Parkinson disease by moderating oxidative stress and protein aggregation. Dopamine cell death in Parkinson disease (PD)3 results from both genetic and environmental factors (1-5). Six genes have been linked to PD including ␣-synuclein, Parkin, UCHL1, DJ-1, PINK1, and LRRK2 (6 -7). ␣-Synuclein mutations (A53T, A30P, and E46K) cause autosomal dominant forms of PD (8 -10). Even in sporadic cases of PD, aggregated ␣-synuclein has been found to be a major component of Lewy bodies (11-13). The toxicity of mutant forms of ␣-synuclein results from increased formation of oligomeric and fibrillar aggregates (14 -17). We and others (18 -22) have demonstrated that expression of A53T mutant ␣-synuclein results in protein aggregation and cell death in cultured dopamine neurons.Mutations in the DJ-1 gene (PARK7) lead to early-onset, autosomal recessive Parkinson disease (23-26). Ordinarily, DJ-1 protects cells by a number of mechanisms. The protein can self-oxidize by forming cysteine-sulfinic acid under oxidizing conditions, thereby shifting its pI from 6.1 to 5.8 (27-28). DJ-1 can sequester the cell death protein Daxx and prevent Daxx-induced apoptosis after oxidative stress (29). DJ-1 can stabilize Nrf2 (nuclear factor erythroid 2-related factor) by preventing association with its inhibitor protein, Keap1, thereby blocking the subsequent ubiquitination of Nrf2 (30).Previously, we have reported that overexpression of WT DJ-1 can prote...

Costs and successful field performance need to be weighed against the added data detail gained from monitoring equipment when making choices about exposure assessment techniques for epidemiological studies.

No abstract

Sister chromatid cohesion (SCC), efficient DNA repair, and the regulation of some metazoan genes require the association of cohesins with chromosomes. Cohesins are deposited by a conserved heterodimeric loading complex composed of the Scc2 and Scc4 proteins in Saccharomyces cerevisiae, but how the Scc2/Scc4 deposition complex regulates the spatiotemporal association of cohesin with chromosomes is not understood. We examined Scc2 chromatin association during the cell division cycle and found that the affinity of Scc2 for chromatin increases biphasically during the cell cycle, increasing first transiently in late G 1 phase and then again later in G 2 /M. Inactivation of Scc2 following DNA replication reduces cellular viability, suggesting that this post S-phase increase in Scc2 chromatin binding affinity is biologically relevant. Interestingly, high and low Scc2 chromatin binding levels correlate strongly with the presence of full-length or amino-terminally cleaved forms of Scc2, respectively, and the appearance of the cleaved Scc2 species is promoted in vitro either by treatment with specific cell cycle-staged cellular extracts or by dephosphorylation. Importantly, Scc2 cleavage eliminates Scc2-Scc4 physical interactions, and an scc2 truncation mutant that mimics in vivo Scc2 cleavage is defective for cohesin deposition. These observations suggest a previously unidentified mechanism for the spatiotemporal regulation of cohesin association with chromosomes through cell cycle regulation of Scc2 cohesin deposition activity by Scc2 dephosphorylation and cleavage.M ultisubunit, ring-shaped cohesin complexes play key roles in chromosome morphogenesis that are required for faithful chromosome transmission to daughter cells. Newly replicated sister chromatids become tethered together by cohesins during S phase, which promotes chromosome biorientation on mitotic spindles (1). Cohesins also mediate efficient DNA double-strand break repair by homologous recombination (2, 3) and the formation or stabilization of chromatin loops that affect various nuclear processes, such as gene expression and Ig gene rearrangements (reviewed in refs. 4 and 5). Altered gene expression resulting from defective cohesinmediated chromatin looping is likely responsible for the pathogenesis of Cornelia de Lange Syndrome (CdLS), a dominantly inherited human developmental disorder (6).Sister chromatid cohesion (Scc) proteins form a heterodimeric cohesin deposition complex, but the complex's activity in deposition is not understood (7). Cohesins copurify with Scc2/Scc4, suggesting that Scc2/Scc4 plays a direct role in deposition (8-11). In the absence of either loader complex subunit, cohesin rings assemble, but fail to be deposited (7,12,13). ATP hydrolysis by cohesin's structural maintenance of chromosome (SMC) subunits is required for cohesin loading, and deposition is inhibited when SMC hinge domains, which mediate Smc1/3 interactions within cohesin, are artificially tethered (8,14,15). Thus, Scc2/ Scc4 may activate cohesin's ATPase activity or f...