Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation

Concepedia

Stephen W. Davies, Mark Turmaine, Barbara A. Cozens, Marian DiFiglia, Alan H. Sharp, Christopher A. Ross, Eberhard Scherzinger, Erich E. Wanker, Laura Mangiarini, Gillian P. Bates

Cell · 1997 · 2.2K citations · 48 references

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TL;DR

Huntington's disease is a neurodegenerative disorder caused by a CAG/polyglutamine repeat expansion in an otherwise uncharacterized gene, and the mechanism underlying its delayed onset, selective neuropathology, and cell death remains unknown. Transgenic mice expressing human HD exon 1 with 115–156 CAG repeats form huntingtin‑ and ubiquitin‑rich neuronal intranuclear inclusions before any neurological symptoms, mirroring the nuclear abnormalities seen in HD patient biopsies.

Abstract

Huntington's disease (HD) is one of an increasing number of human neurodegenerative disorders caused by a CAG/polyglutamine-repeat expansion. The mutation occurs in a gene of unknown function that is expressed in a wide range of tissues. The molecular mechanism responsible for the delayed onset, selective pattern of neuropathology, and cell death observed in HD has not been described. We have observed that mice transgenic for exon 1 of the human HD gene carrying (CAG)115 to (CAG)156 repeat expansions develop pronounced neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin, prior to developing a neurological phenotype. The appearance in transgenic mice of these inclusions, followed by characteristic morphological change within neuronal nuclei, is strikingly similar to nuclear abnormalities observed in biopsy material from HD patients.