Expression of expanded polyglutamine targets profilin for degradation and alters actin dynamics.

Huntington's disease is caused by polyglutamine expansion in the huntingtin protein. Huntingtin directly interacts with profilin, a major actin monomer sequestering protein and a key integrator of signals leading to actin polymerization. We observed a progressive loss of profilin in the cerebral cortex of Huntington's disease patients, and in cell culture and Drosophila models of polyglutamine disease. This loss of profilin is likely due to increased degradation through the ubiquitin proteasome system. Profilin loss reduces the F/G actin ratio, indicating a shift in actin polymerization. Overexpression of profilin abolishes mutant huntingtin toxicity in cells and partially ameliorates the morphological and functional eye phenotype and extends lifespan in a transgenic polyglutamine Drosophila model. These results indicate a link between huntingtin and profilin and implicate profilin in Huntington's disease pathogenesis.

Acid exposure is an immune disruptor in adult Rana pipiens.

Acidic environments are physiological stressors for amphibians. The objective of the present study was to document the effect of an acidic environment on innate immune system function under controlled experimental conditions in Rana pipiens. We developed an in vivo assay, by injecting a suspension of 1-microm fluorescent beads in fluid thioglycollate, to induce peritonitis. The number of peritoneal exudate leukocytes and their phagocytic activity did not increase with thioglycollate injection when frogs were exposed to pH 5.5 compared to when frogs were exposed to pH 7.0. An environment of pH 5.5 disrupted the inflammatory response of frogs compared to an environment of pH 7.0; at pH 5.5, more nonphagocytic leukocytes and fewer highly phagocytic leukocytes were found compared to those in frogs exposed to pH 7.0. Frogs stimulated by thioglycollate injection and exposed to pH 5.5 had a 50% increase in cells that did not exhibit phagocytosis and a 4- to 10-fold reduction in the number of highly phagocytic cells. This is evidence that acid exposure functions as an immune disruptor in adult R. pipiens under laboratory conditions.

Amyotrophic lateral sclerosis: an emerging era of collaborative gene discovery.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs) that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA), phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS.