Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein.
Intranuclear inclusion bodies are a shared pathological feature of Huntington's disease (HD) and its transgenic mouse model. Using a panel of antibodies spanning the entire huntingtin molecule, we have investigated the pattern of immunoreactivity within the intranuclear inclusions in the frontal cortex and striatum of patients with HD. The intranuclear inclusions reacted with anti-ubiquitin and antibodies against the N-terminal portion of huntingtin (CAG53b, HP1), but not with HD1 and the 1C2 antibodies that detect the expanded polyglutamine tract nor the more C-terminal antibodies. However, the 1C2, HP1, CAG53b, and HD1 antibodies detected granular cytoplasmic deposits in cortical and striatal neurons that also contained intranuclear N-terminal huntingtin immunoreactivity. These data show a differential intracellular location of truncated huntingtin in the HD brain. Both the cytoplasmic and the nuclear aggregates of the protein fragments could be neurotoxic. The frequency of the cortical intranuclear inclusions correlated with the size of CAG expansion and was inversely related to the age at onset and death. No such correlations were detected for the striatum, which most likely reflects a more advanced neuronal loss accrued by the time of death.
Sieradzan
K A
KA
Department of Neurology, The Royal Infirmary, Manchester, United Kingdom.
Mechan
A O
AO
Jones
L
L
Wanker
E E
EE
Nukina
N
N
Mann
D M
DM
D000328:Adult; D000368:Aged; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D000939:Epitopes; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism*; D018911:Trinucleotide Repeats
D000939:Epitopes; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins