TBP, a polyglutamine tract containing protein, accumulates in Alzheimer's disease.
Alzheimer's disease (AD) is characterised by extra cellular beta-amyloid (betaA) deposition, Tau-containing neurofibrillary tangles (NFTs) and progressive cortical atrophy. Abnormal protein accumulation is also a common feature of other late onset neurodegenerative diseases, including the heritable polyglutamine (polyQ) disorders such as Huntington disease (HD) and the spinocerebellar ataxias (SCAs). One of this family of disorders, SCA17, is caused by an expansion of a polymorphic polyQ repeat in TATA binding protein (TBP), an essential transcription factor. Surprisingly, the wild type TBP repeat length ranges from 25 to 42, and in Caucasian populations the most common allele is 38, a size large enough to cause HD if within the huntingtin protein. Wild type length TBP accumulates in HD and in at least some of the SCAs, and consequently we hypothesised that it may contribute to AD. Here we provide evidence that TBP accumulates in AD brain, localising to neurofibrillary tangle structures. A proportion of TBP present in AD brain is insoluble; a signature of the polyQ diseases. TBP is present differentially between patients and its amount and distribution is not directly proportional to that of Tau or beta-amyloid positive structures. We present this as evidence for the hypothesis that the accumulation or misfolding of this polyQ containing protein may be a contributing factor in Alzheimer's disease.
Reid
Suzanne J
SJ
Department of Pharmacology, Medical Health Sciences Campus, University of Auckland, New Zealand.
van Roon-Mom
Willeke M C
WM
Wood
Phil C
PC
Rees
Mark I
MI
Owen
Michael J
MJ
Faull
Richard L M
RL
Dragunow
Mike
M
Snell
Russell G
RG
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D035181:TATA-Box Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010455:Peptides; D035181:TATA-Box Binding Protein; D016875:tau Proteins; C097188:polyglutamine