From neuronal inclusions to neurodegeneration: neuropathological investigation of a transgenic mouse model of Huntington'sdisease

Author:

Davies Stephen W.1,Mark Turmaine1,Cozens Barbara A.1,Raza Aysha S.1,Mahal Amarbirpal2,Mangiarini Laura2,Bates Gillian P.2

Affiliation:

1. Department of Anatomy and Developmental Biology, University College London, Gower Street, LondonWC1E 6BT, UK

2. Medical and Molecular Genetics, GKTMedical and Dental School, King'sCollege, 8th Floor, Guy's Tower, London SE1 9RT, UK

Abstract

Huntington'sdisease (HD) is an inherited progressive neurodegenerative disease caused by the expansion of a polyglutamine repeat sequence within a novel protein. Recent work has shown that abnormal intranuclear inclusions of aggregated mutant protein within neurons is a characteristic feature shared by HD and several other diseases involving glutamine repeat expansion. This suggests that in each of the these disorders the affected nerve cells degenerate as a result of these abnormal inclusions. A transgenic mouse model of HD has been generated by introducing exon 1 of the HD gene containing a highly expanded CAG sequence into the mouse germline. These mice develop widespread neuronal intranuclear inclusions and neurodegeneration specifically within those areas of the brain known to degenerate in HD. We have investigated the sequence of pathological changes that occur after the formation of nuclear inclusions and that precede neuronal cell death in these cells. Although the relation between inclusion formation and neurodegeneration has recently been questioned, a full characterization of the pathways linking protein aggregation and cell death will resolve some of these controversies and will additionally provide new targets for potential therapies.

Publisher

The Royal Society

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology

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