Recent studies have begun to focus on the signals that regulate axonal protein synthesis and the functional significance of localized protein synthesis. However, identification of proteins that are synthesized in mammalian axons has been mainly based on predictions. Here, we used axons purified from cultures of injury-conditioned adult dorsal root ganglion (DRG) neurons and proteomics methodology to identify axonally synthesized proteins. Reverse transcription (RT)-PCR from axonal preparations was used to confirm that the mRNA for each identified protein extended into the DRG axons. Proteins and the encoding mRNAs for the cytoskeletal proteins ␤-actin, peripherin, vimentin, ␥-tropomyosin 3, and cofilin 1 were present in the axonal preparations. In addition to the cytoskeletal elements, several heat shock proteins (HSP27, HSP60, HSP70, grp75, ␣B crystallin), resident endoplasmic reticulum (ER) proteins (calreticulin, grp78/BiP, ERp29), proteins associated with neurodegenerative diseases (ubiquitin C-terminal hydrolase L1, rat ortholog of human DJ-1/Park7, ␥-synuclein, superoxide dismutase 1), anti-oxidant proteins (peroxiredoxins 1 and 6), and metabolic proteins (e.g., phosphoglycerate kinase 1 (PGK 1), ␣ enolase, aldolase C/Zebrin II) were included among the axonally synthesized proteins. Detection of the mRNAs encoding each of the axonally synthesized proteins identified by mass spectrometry in the axonal compartment indicates that the DRG axons have the potential to synthesize a complex population of proteins. Local treatment of the DRG axons with NGF or BDNF increased levels of cytoskeletal mRNAs into the axonal compartment by twofold to fivefold but had no effect on levels of the other axonal mRNAs studied. Neurotrophins selectively increased transport of ␤-actin, peripherin, and vimentin mRNAs from the cell body into the axons rather than changing transcription or mRNA survival in the axonal compartment.

Rationale: Interpatient variability in montelukast response may be related to variation in leukotriene pathway candidate genes. Objective: To determine associations between polymorphisms in leukotriene pathway candidate genes with outcomes in patients with asthma receiving montelukast for 6 mo who participated in a clinical trial. Methods: Polymorphisms were typed using Sequenom matrixassisted laser desorption/ionization time-of-flight (MALDI-TOF) mass array spectrometry and published methods; haplotypes were imputed using single nucleotide polymorphism-expectation maximization (SNP-EM). Analysis of variance and logistic regression models were used to test for changes in outcomes by genotype. In addition, 2 and likelihood ratio tests were used to test for differences between groups. Case-control comparisons were analyzed using the SNP-EM Omnibus likelihood ratio test. Measurements: Outcomes were asthma exacerbation rate and changes in FEV 1 compared with baseline. Results: DNA was collected from 252 participants: 69% were white, 26% were African American. Twenty-eight SNPs in the ALOX5, LTA4H, LTC4S, MRP1, and cysLT1R genes, and an ALOX5 repeat polymorphism were successfully typed. There were racial disparities in allele frequencies in 17 SNPs and in the repeat polymorphism. Association analyses were performed in 61 whites. Associations were found between genotypes of SNPs in the ALOX5 (rs2115819) and MRP1 (rs119774) genes and changes in FEV 1 (p Ͻ 0.05), and between two SNPs in LTC4S (rs730012) and in LTA4H (rs2660845) genes for exacerbation rates. Mutant ALOX5 repeat polymorphism was associated with decreased exacerbation rates. There was strong linkage disequilibrium between ALOX5 SNPs. Associations between ALOX5 haplotypes and risk of exacerbations were found. Conclusions: Genetic variation in leukotriene pathway candidate genes contributes to variability in montelukast response. Keywords: antiinflammatory; montelukast; pharmacodynamic; pharmacogeneticMontelukast is a selective cysteinyl leukotriene 1 (cysLT 1 ) receptor antagonist (1). Montelukast is recommended as an alternative to low-dose inhaled corticosteroids for patients with mild persis- tent asthma and recommended as alternative add-on (to inhaled corticosteroids) treatment in patients with moderate persistent (step 3) and severe persistent (step 4) asthma (2). Numerous clinical trials in adults and children with asthma have established the efficacy and safety of montelukast (3, 4). However, interpatient variability in response to montelukast in both children and adults with asthma is significant, with 35 to 78% of patients receiving montelukast being classified as nonresponders (5-7). The mechanisms underlying interpatient variability in response are not clear but are believed to be due, in part, to genetic variability (8-11). Indeed, several studies have reported that promoter polymorphisms in the ALOX5 (12) and the LTC 4 synthase (LTC4S) genes contribute to variability in response to LT modifiers and LT selective antagonists (13)(14)(15)(16).Cy...