The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: Neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis

Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine expansion in the protein huntingtin (htt). Pathogenesis in HD appears to involve the formation of ubiquitinated neuronal intranuclear inclusions containing N-terminal mutated htt, abnormal protein interactions, and the aggregate sequestration of a variety of proteins (noticeably, transcription factors). To identify novel htt-interacting proteins in a simple model system, we used a yeast two-hybrid screen with a Caenorhabditis elegans activation domain library. We found a predicted WW domain protein (ZK1127.9) that interacts with N-terminal fragments of htt in two-hybrid tests. A human homologue of ZK1127.9 is CA150, a transcriptional coactivator with a N-terminal insertion that contains an imperfect (Gln-Ala)38 tract encoded by a polymorphic repeat DNA. CA150 interacted in vitro with full-length htt from lymphoblastoid cells. The expression of CA150, measured immunohistochemically, was markedly increased in human HD brain tissue compared with normal age-matched human brain tissue, and CA150 showed aggregate formation with partial colocalization to ubiquitin-positive aggregates. In 432 HD patients, the CA150 repeat length explains a small, but statistically significant, amount of the variability in the onset age. Our data suggest that abnormal expression of CA150, mediated by interaction with polyglutamine-expanded htt, may alter transcription and have a role in HD pathogenesis.

Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington's disease

This investigation was pursued to test the use of intracellular antibodies (intrabodies) as a means of blocking the pathogenesis of Huntington's disease (HD). HD is characterized by abnormally elongated polyglutamine near the N terminus of the huntingtin protein, which induces pathological protein–protein interactions and aggregate formation by huntingtin or its exon 1-containing fragments. Selection from a large human phage display library yielded a single-chain Fv (sFv) antibody specific for the 17 N-terminal residues of huntingtin, adjacent to the polyglutamine in HD exon 1. This anti-huntingtin sFv intrabody was tested in a cellular model of the disease in which huntingtin exon 1 had been fused to green fluorescent protein (GFP). Expression of expanded repeat HD-polyQ-GFP in transfected cells shows perinuclear aggregation similar to human HD pathology, which worsens with increasing polyglutamine length; the number of aggregates in these transfected cells provided a quantifiable model of HD for this study. Coexpression of anti-huntingtin sFv intrabodies with the abnormal huntingtin-GFP fusion protein dramatically reduced the number of aggregates, compared with controls lacking the intrabody. Anti-huntingtin sFv fused with a nuclear localization signal retargeted huntingtin analogues to cell nuclei, providing further evidence of the anti-huntingtin sFv specificity and of its capacity to redirect the subcellular localization of exon 1. This study suggests that intrabody-mediated modulation of abnormal neuronal proteins may contribute to the treatment of neurodegenerative diseases such as HD, Alzheimer's, Parkinson's, prion disease, and the spinocerebellar ataxias.

Ciliary neurotrophic factor protects striatal output neurons in an animal model of Huntington disease.

Huntington disease is a dominantly inherited, untreatable neurological disorder featuring a progressive loss of striatal output neurons that results in dyskinesia, cognitive decline, and, ultimately, death. Neurotrophic factors have recently been shown to be protective in several animal models of neurodegenerative disease, raising the possibility that such substances might also sustain the survival of compromised striatal output neurons. We determined whether intracerebral administration of brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3, or ciliary neurotrophic factor could protect striatal output neurons in a rodent model of Huntington disease. Whereas treatment with brain-derived neurotrophic factor, nerve growth factor, or neurotrophin-3 provided no protection of striatal output neurons from death induced by intrastriatal injection of quinolinic acid, an N-methyl-D-aspartate glutamate receptor agonist, treatment with ciliary neurotrophic factor afforded marked protection against this neurodegenerative insult.

Los conflictos internacionales con Irán y Corea del Norte (I): el proceso negociador

El artículo detalla el proceso de negociación llevado a cabo para solucionar el conflicto creado por las pretensiones nucleares de Irán y la República Popular de Corea, así como el contexto político y de seguridad regional. El artículo está dividido en dos partes. La primera parte que se publica en este número detalla, en lo posible, el proceso negociador, las propuestas presentadas y las posiciones contrapuestas. Para su recto entendimiento se explican los dilemas y las líneas rojas establecidas por la Administración estadounidense, que van más allá de lo que establece el Tratado de No Proliferación; así como las razones de esta postura: el programa nuclear clandestino de Irán, la “admisión” de la existencia de un programa de enriquecimiento nuclear clandestino en el caso de la República Popular de Corea. Se analizan así los presupuestos, las carencias negociadoras, la falta de garantías de seguridad y la profunda desconfianza existente en estos dos Estados con respecto a las políticas e intenciones de los Estados Unidos. Una segunda parte explicará con más detalle las implicaciones políticas y de seguridad regional.

Accounts with Benjamin Huntington, 1785-1787

This folder contains two handwritten copies of the accounts between Reverend Andrew Croswell of Boston, and Croswell's executor William Croswell, and Benjamin Huntington, for money collected from Col. Gallup between 1785 and 1787.

Professor David Huntington with FE Church painting "Syria by the Sea"

Huntington was a respected scholar of American painter Frederick Edwin Church

Rules how to compose : a facsimile edition of a manuscript from the library of the Earl of Bridgewater (circa 1610) now in the Huntington Library, San Marino, California /

Mode of access: Internet.

Life in Corea,

Mode of access: Internet.

Railroad accident report : Long Island Rail Road Company door accident, Huntington Station, New York, December 1, 1974 /

"SS-R-35"

The Huntington family in America; a genealogical memoir of the known descendants of Simon Huntington from 1633 to 1915, including those who have retained the family name, and many bearing other surnames.

"Constitution of the Huntington family association": p. 7-8.

The death of Robert, Earl of Huntington.: 1601.

Original title: The death of Robert, earl of Huntington. Otherwise called Robin Hood of merry Sherwood; with the lamentable Tragedy of chaste Matilda his fair maid Marian, poisoned at Dunmowe by King John. Acted by the Right Honourable, the Earle of Notingham, Lord high Admiral of England, his servants. Imprinted at London, for William Leake, 1901.

The death of Robert Earl of Huntington /

"Edition": p. 99.

Public health assessment, Huntington Landfill, Town of Huntington, Suffolk County, New York /

"Cerclis No. NYD980506844."

Memoirs of the late Mrs. Susan Huntington, of Boston, Mass. microform /

Checklist Amer. imprints