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Lymphoblasts from patients with Huntington disease exhibit increased mitochondrial depolarization and cell death when subjected to stress. This illustrates that the gene defect that causes the disease affects other organs besides the brain.

Research has been undertaken into the CAG/polyglutamine-repeat expansion which is responsible for the human neurodegenerative disorder Huntington's disease (HD). It was established that mice transgenic for exon 1 of the human HD gene carrying (CAG)115 to (CAG)156 repeat expansions show clear neuronal intranuclear inclusions (NIIs) before developing a neurological phenotype. Neurons within the striatum of mice transgenic for the HD mutation contain an NII that contains the proteins htt and ubiquitin.

A protein that binds to a huntingtin gene and whose binding is enriched by an expanded polyglutamine repeat is analyzed in relation to its link to the pathological study of the brain in Huntington's disease. The disorder involves the expansion of the polyglutamine repeat which has toxic effects. The huntingtin gene's function has not been fully identified although its role in genetic development is acknowledged.

Immunocytochemistry proves the expression of inositol 1,4,5-trisphosphate receptor subtype 3 (IP3R-3) in pancreatic islets. Immunogold electron microscopy helps localize these cells to the secretory granules of insulin-secreting beta cells and somatostatin secretory granules. Localization studies reveal the involvement of granule Ca(2+) stores in the secretory process, which is regulated by IP3R-3. Diabetes and fasting or refeeding increases IP3R-3 levels in islets and glucose increases IP3R-3 levels in insulinoma cells.

Sequence and Expression of mRNAs Encoding the α.sub.1 and α.sub.2 Subunits of a DHP-Sensitive Calcium Channel THE L-TYPE BUT NOT THE T-TYPE OR N-type Ca.sup.2+ channels are sensitive to 'Ca.sup.2+ [...]

Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of a glutamine repeat in the N-terminus of the huntingtin protein. To gain insight into the pathogenesis of HD, we generated transgenic mice that express a cDNA encoding an N-terminal fragment (171 amino acids) of huntingtin with 82, 44 or 18 glutamines. Mice expressing relatively low steady-state levels of N171 huntingtin with 82 glutamine repeats (N171-82Q) develop behavioral abnormalities, including loss of coordination, tremors, hypokinesis and abnormal gait, before dying prematurely. In mice exhibiting these abnormalities, diffuse nuclear labeling, intranuclear inclusions and neuritic aggregates, all immunoreactive with an antibody to the N-terminus (amino acids 1-17) of huntingtin (AP194), were found in multiple populations of neurons. None of these behavioral or pathological phenotypes were seen in mice expressing N171-18Q. These findings are consistent with the idea that N-terminal fragments of huntingtin with a repeat expansion are toxic to neurons, and that N-terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates. [ABSTRACT FROM AUTHOR]

Develops a cell culture model demonstrating that N-terminal fragments of huntingtin with expanded glutamine repeats aggregate both in the cytoplasm and in the nucleus in Huntington's disease. Overview of the disorder; Cellular expression and aggregation; Cellular toxicity; Cellular localization.

Complementary DNAs were isolated and used to deduce the primary structures of the α1 and α2 subunits of the dihydropyridine-sensitive, voltage-dependent calcium channel from rabbit skeletal muscle. The α1 subunit, which contains putative binding sites for calcium antagonists, is a hydrophobic protein with a sequence that is consistent with multiple transmembrane domains and shows structural and sequence homology with other voltage-dependent ion channels. In contrast, the α2 subunit is a hydrophilic protein without homology to other known protein sequences. Nucleic acid hybridization studies suggest that the α1 and α2 subunit mRNAs are expressed differentially in a tissue-specific manner and that there is a family of genes encoding additional calcium channel subtypes. [ABSTRACT FROM AUTHOR]