Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation.
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.
Davies
S W
SW
Department of Anatomy and Developmental Biology, University College London, United Kingdom.
Turmaine
M
M
Cozens
B A
BA
DiFiglia
M
M
Sharp
A H
AH
Ross
C A
CA
Scherzinger
E
E
Wanker
E E
EE
Mangiarini
L
L
Bates
G P
GP
D000818:Animals; D001921:Brain / Q000473:pathology*; D002467:Cell Nucleus / Q000473:pathology / Q000648:ultrastructure*; D018450:Disease Progression; D005091:Exons; D006720:Homozygote; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000473:pathology / Q000648:ultrastructure*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure*; D009687:Nuclear Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid; D014452:Ubiquitins / Q000032:analysis; D015431:Weight Loss
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014452:Ubiquitins