Open AccessTransgenic Mice in the Study of Polyglutamine Repeat Expansion Diseases
Author(s) -
Bates Gillian P.,
Mangiarini Laura,
Davies Stephen W.
Publication year - 1998
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/j.1750-3639.1998.tb00196.x
Subject(s) - neurodegeneration , huntingtin , genetically modified mouse , trinucleotide repeat expansion , transgene , phenotype , polyglutamine tract , huntingtin protein , exon , biology , huntington's disease , microbiology and biotechnology , gene , pathology , genetics , disease , medicine , allele
An increasing number of neurodegenerative diseases, including Huntington's disease (HD), have been found to be caused by a CAG/polyglutamine expansion. We have generated a mouse model of HD by the introduction of exon 1 of the human HD gene carrying highly expanded CAG repeats into the mouse germ line. These mice develop a progressive neurological phenotype. Neuronal intranuclear inclusions (NII) that are immunoreactive for huntingtin and ubiquitin have been found in the brains of symptomatic mice. In vitro analysis indicates that the inclusions are formed through self aggregation via the polyglutamine repeat into amyloid‐like fibrils composed of a cross β‐sheet structure that has been termed a polar zipper. Analysis of patient material and other transgenic lines has now shown NII to be a common feature of all of these diseases. In the transgenic models, inclusions are present prior to the onset of symptoms suggesting a causal relationship. In contrast, neurodegeneration occurs after the onset of the phenotype indicating that the symptoms are caused by a neuronal dysfunction rather than a primary cell death.