Alexander's disease, a leukodystrophy characterized by Rosenthal fibers (RFs) in the brain, is categorized into three subtypes: infantile, juvenile, and adult. Although most are sporadic, occasional familial Alexander's disease cases have been reported for each subtype. Hereditary adult-onset Alexander's disease shows progressive spastic paresis, bulbar or pseudobulbar palsy, palatal myoclonus symptomatologically, and prominent atrophy of the medulla oblongata and upper spinal cord on magnetic resonance imaging. Recent identification of GFAP gene mutations in the sporadic infantile- and juvenile-onset Alexander's disease prompted us to examine the GFAP gene in two Japanese hereditary adult-onset Alexander's disease brothers with autopsy in one case. Both had spastic paresis without palatal myoclonus, and magnetic resonance imaging showed marked atrophy of the medulla oblongata and cervicothoracic cord. The autopsy showed severely involved shrunken pyramids, but scarce Rosenthal fibers (RFs). Moderate numbers of Rosenthal fibers (RFs) were observed in the stratum subcallosum and hippocampal fimbria. In both cases, we found a novel missense mutation of a G-to-T transition at nucleotide 841 in the GFAP gene that results in the substitution of arginine for leucine at amino acid residue 276 (R276L). This is the first report of identification of the causative mutation of the GFAP gene for neuropathologically proven hereditary adult-onset Alexander's disease, suggesting a common molecular mechanism underlies the three Alexander's disease subtypes.

Mulberry latex contains extremely high concentrations of alkaloidal sugar mimic glycosidase inhibitors, such as 1,4-dideoxy-1,4-imino-D-arabinitol (D-AB1) and 1-deoxynojirimycin (DNJ).Although these compounds do not harm the silkworm, Bombyx mori, a mulberry specialist, they are highly toxic to insects that do not normally feed on mulberry leaves. D-AB1 and DNJ are strong inhibitors of ␣-glucosidases (EC 3.2.1.20); however, they do not affect the activity of ␤-fructofuranosidases (EC 3.2.1.26). Although ␣-glucosidase genes are found in a wide range of organisms, ␤-fructofuranosidase genes have not been identified in any animals so far. In this study, we report the identification and characterization of ␤-fructofuranosidase genes (BmSuc1 and BmSuc2) from B. mori. The BmSuc1 gene was highly expressed in the midgut and silk gland, whereas the expression of BmSuc2 gene was not detected. BmSuc1 encodes a functional ␤-fructofuranosidase, whose enzymatic activity was not inhibitedbyDNJorD-AB1.WealsoshowedthatBmSUC1proteinlocalized within the midgut goblet cell cavities. Collectively, our data clearly demonstrated that BmSuc1 serves as a sugar-digesting enzyme in the silkworm physiology. This anomalous presence of the ␤-fructofuranosidase gene in the B. mori genome may partly explain why the silkworm can circumvent the mulberry's defense system.Certain plants have evolved defense mechanisms against insect predation through the production of defense compounds (1-3). This is reflected by the limited number of insects capable of feeding on such plants. In particular, plant latex often contains a wide variety of toxic compounds, such as alkaloids and proteases, which play an important role in a plant's defense mechanism against insect herbivory (2, 4 -6).Mulberry latex contains extremely high concentrations of alkaloidal sugar mimic glycosidase inhibitors, such as 1,4-2 1-deoxynojirimycin (DNJ), and 1,4-dideoxy-1,4-imino-D-ribitol (2, 7). These sugar mimic alkaloids are not toxic to larvae of the silkworm Bombyx mori (family Bombycidae), which feed only on mulberry leaves and have been reared on them for thousands of years (2). However, these compounds are highly toxic to other caterpillars, such as the eri-silkworm Samia cynthia ricini (family Saturniidae) and cabbage moth Mamestra brassicae (family Noctuidae), for which mulberry trees are not the host plant in natural conditions (2). This indicates that the silkworm has evolved an unknown mechanism to circumvent the toxic effects of such sugar mimic alkaloids, thus enabling it to feed and grow well on mulberry leaves (2, 8).Sucrases are digestive enzymes that hydrolyze ␣-glucosyl (␣-glucosidase, EC 3.2.1.20) or ␤-fructosyl residue (␤-fructofuranosidase, EC 3.2.1.26) of the substrate. D-AB1 and DNJ are strong inhibitors of ␣-glucosidases; however, they do not exhibit inhibitory activity against ␤-fructofuranosidases (7). Although ␣-glucosidases are found in many types of organisms, including bacteria, fungi, plants, and animals, it has been generally assumed that ␤-fructof...

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How left–right (LR) asymmetric forms in the animal body is a fundamental problem in Developmental Biology. Although the mechanisms for LR asymmetry are well studied in some species, they are still poorly understood in invertebrates. We previously showed that the intrinsic LR asymmetry of cells (designated as cell chirality) drives LR asymmetric development in the Drosophila embryonic hindgut, although the machinery of the cell chirality formation remains elusive. Here, we found that the Drosophila homologue of the Id gene, extra macrochaetae (emc), is required for the normal LR asymmetric morphogenesis of this organ. Id proteins, including Emc, are known to interact with and inhibit E‐box‐binding proteins (E proteins), such as Drosophila Daughterless (Da). We found that the suppression of da by wild‐type emc was essential for cell chirality formation and for normal LR asymmetric development of the embryonic hindgut. Myosin ID (MyoID), which encodes the Drosophila Myosin ID protein, is known to regulate cell chirality. We further showed that Emc‐Da regulates cell chirality formation, in which Emc functions upstream of or parallel to MyoID. Abnormal Id‐E protein regulation is involved in various human diseases. Our results suggest that defects in cell shape may contribute to the pathogenesis of such diseases.

The lesions of fibrocontractive diseases result from an excessive myofibroproliferative response to numerous forms of inflammatory stimuli, which elicit the net deposition of extracellular matrix (ECM) in the interstitium of the affected tissue. Hyaluronan (HA), reported to be a key player supporting cellular migration and adherence, is a major component of ECM that undergoes dynamic regulation during inflammation. The molecular regulation of HA biosynthesis by inflammatory cytokines on myofibroblasts is not yet completely understood. Here we report the biochemical characteristics of the lung myofibroblast cell line MRC-5, and we demonstrate that the production of HA by this cell line is inducible by the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), at the message level of HA synthase (HAS). In TNF-alpha-stimulated MRC-5 cells, DNA-binding and competition experiments indicated that the predominant NF-kappa B binding activity detected with nuclear extract-stimulated cells is mediated by the p50/p65 complex. Using antisense oligonucleotides, we confirmed that the TNF-alpha-stimulation of HA synthesis by MRC-5 cells is dependent on the activation of the p50/p65 NF-kappa B complex. These findings indicate that TNF-alpha production within inflamed tissues may enhance the HA synthesis via the transcriptional induction of HAS on myofibroblasts, thereby providing a provisional matrix for supporting cellular migration and adhesion, and that the p50/p65 NF-kappa B complex that plays an important role in the regulation of HA production by TNF-alpha might be an appropriate target for therapeutic compounds to treat tissue fibrosis accompanied by inflammation.