At least eight inherited neurodegenerative diseases are caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches are implicated, the molecular mechanisms of neurodegeneration remain unclear. We found that expanded polyQ stretches preferentially bind to TAFII130, a coactivator involved in cAMP-responsive element binding protein (CREB)-dependent transcriptional activation, and strongly suppress CREB-dependent transcriptional activation. The suppression of CREB-dependent transcription and the cell death induced by polyQ stretches were restored by the co-expression of TAFII130. Our results indicate that interference of transcription by the binding of TAFII130 with expanded polyQ stretches is involved in the pathogenetic mechanisms underlying neurodegeneration.

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.

Ganglioside G M3 is a major glycosphingolipid in the plasma membrane and is widely distributed in vertebrates. We describe here the isolation of a human cDNA whose protein product is responsible for the synthesis of G M3 . The cloned cDNA spanned 2,359 base pairs, with an open reading frame encoding a protein of 362 amino acids with a predicted molecular mass of 41.7 kDa. The deduced primary structure shows features characteristic of the sialyltransferase family, including a type II transmembrane topology and the sialylmotifs L at the center and S at the C-terminal region. An amino acid substitution from aspartic acid to histidine was demonstrated at a position invariant in sialylmotif L of all the other sialyltransferases so far cloned. The best acceptor substrate for the gene product was lactosylceramide, and cells transfected with the cloned cDNA clearly exhibited de novo synthesis of G M3 , with a measurable decrease in the precursor lactosylceramide. Despite the ubiquitous distribution of ganglioside G M3 in human tissues, a major 2.4-kilobase transcript of the gene was found in a tissue-specific manner, with predominant expression in brain, skeletal muscle, and testis, and very low expression in liver.It is known that sialic acid-containing glycosphingolipids, gangliosides, have various important biological functions (1, 2), and their functions as well as their biosynthesis are currently clarified. In vertebrates, almost all the ganglio-series gangliosides are synthesized from a common precursor, ganglioside G M3 , 1 which has the simplest structure among the major gangliosides. G M3 itself is known to participate in induction of differentiation (3, 4), modulation of proliferation (2, 5), maintenance of fibroblast morphology (6), signal transduction (7), and integrin-mediated cell adhesion (8).Molecular cloning of genes whose protein products catalyze the transfer of sialic acid through an ␣-2,3 linkage has been reported (14 -17), and these protein products had the same acceptor substrates, i.e. the oligosaccharides of O-and N-linked glycoproteins and glycolipids. However, none of the gene products so far reported is known to be involved in the synthesis of ganglioside G M3 . We demonstrated previously that the level of G M3 synthase activity was dramatically enhanced during the monocytic differentiation of . Using a cDNA library prepared from the differentiated HL-60 cells, we have isolated a cDNA encoding the G M3 synthase by a modified expression cloning method. In the present study, we demonstrate that the G M3 synthase shows some features clearly distinct from those of all the other sialyltransferases so far cloned, although it possesses several features common to members of the sialyltransferase family. MATERIALS AND METHODSCell Culture-The human myelogenous leukemia cell line HL-60, and the mouse lung carcinoma cell line 3LL-J5 (22), which completely lacks acidic glycosphingolipids, and its derivative cell lines, 3LL-HK46, which stably expresses the polyoma virus large tumor antigen, and 3LL-ST28, w...

The authors describe two Japanese siblings with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) without spasticity, usually a core feature of this disorder. They had a novel homozygous missense mutation (T987C) of the SACS gene, which resulted in a phenylalanine-to-serine substitution at amino acid residue 304.

We found clinical heterogeneity in the patients with EAOH in this study. With the disease course, the choreiform movements tended to reduce in degree, and hypoalbuminemia became evident. Molecular analysis identified one insertion and two missense mutations including a novel missense one, which was located at a highly conserved amino acid residue in the aprataxin gene product.