TATA binding protein in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a late onset neurodegenerative disorder, affecting tens of thousands of people in New Zealand, as well as their families and caregivers. AD is characterised by extra cellular β-amyloid (βA) 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 25-42, 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 the disease structures of HD and in at least some of the SCAs. The work described in this thesis investigates the hypothesis that the TATA binding protein (TBP) contributes to AD. This thesis describes the discovery that TBP accumulates in AD brain, localising to NFTs. Also, a proportion of the detectable TBP present is insoluble; a signature of the polyQ diseases. TBP positive structures are shown to be present differentially between patients and its amount and distribution is not directly proportional to that of Tau or β-amyloid positive structures. To investigate if the polyQ repeat length in TBP is associated with AD, alleles were genotyped from two large case/control cohorts. In one cohort, but not the other, older patients carried longer TBP polyQ repeats than controls, and the effect was enhanced when subjects homozygous for the ApoE4 allele were removed from the dataset. Evidence is presented that transcriptional activation by HMGBI, a chromatin associated protein that binds to the polyQ tract within TBP, is altered when co-expressed with TBP carrying 90 glutamines. Taken together this data provides evidence for the hypothesis that the accumulation or misfolding of this polyQ containing protein may be a contributing factor in Alzheimer's disease.