Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length.
Huntington's disease (HD) is caused by CAG triplet repeat expansion in IT15 which leads to polyglutamine stretches in the HD protein product, huntingtin. The pathological hallmark of HD is the degeneration of subsets of neurons, primarily those in the striatum and neocortex. Specific morphological markers of affected cells have not been identified in patients with HD, although a unique itranuclear inclusion was recently reported in neurons of transgenic animals expressing a construct encoding the N-terminal part (including the glutamine repeat) of huntingtin (Davies et al., 1997). In order to understand the importance of this finding, we sought for comparable nuclear abnormalities in autopsy material from patients with HD. In all 20 HD cases examined, anti-ubiquitin and N-terminal huntingtin antibodies identified itranuclear inclusions in neurons and the frequency of these lesions correlated with the length of the CAG repeat in IT15. In addition, examination of material from the related HD-like triplet repeat disorder, dentatorubral and pallidoluysian atrophy, also revealed intranuclear neuronal inclusions. These findings suggest that intranuclear inclusions containing protein aggregates may be common feature of the pathogenesis of glutamine repeat neurodegenerative disorders.
Becher
M W
MW
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA. mbecher@welchlink.welch.jhu.edu
Kotzuk
J A
JA
Sharp
A H
AH
Davies
S W
SW
Bates
G P
GP
Price
D L
DL
Ross
C A
CA
D000293:Adolescent; D000328:Adult; D000368:Aged; D001284:Atrophy; D002648:Child; D018891:Dentate Gyrus / Q000473:pathology; D005917:Globus Pallidus / Q000473:pathology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology*; D002479:Inclusion Bodies / Q000737:chemistry / Q000473:pathology*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics; D009474:Neurons / Q000473:pathology*; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics; D012012:Red Nucleus / Q000473:pathology; D018911:Trinucleotide Repeats; D014452:Ubiquitins / Q000032:analysis
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014452:Ubiquitins