Transcription Factor Sequestration by Polyglutamine Proteins - Protein Misfolding and Cellular Stress in Disease and Aging - page 207

Chapter 14
Transcription Factor Sequestration by Polyglutamine
Proteins
Tomoyuki Yamanaka and Nobuyuki Nukina
Abstract
In polyglutamine diseases including Huntington's disease, the causative gene products containing
expanded polyglutamine form nuclear aggregates in neurons. Recent studies have identified several tran-
scriptional factors, which interact with and are sequestered by expanded polyglutamine aggregates in
neurons. Further, altered expression of many genes has been shown in several polyglutamine disease
models. These observations suggest an involvement of transcriptional dysregulation in pathological pro-
cess of these diseases. In this chapter, we introduce several methods to examine the interaction of tran-
scriptional factors with and their sequestration by expanded polyglutamine proteins in vitro and in vivo.
Key words: Polyglutamine, Huntington's disease, Huntingtin, Transcriptional factor, Sequestration,
Aggregate, Western blot analysis, Filter trap assay, Immunofluorescence microscopy, EMSA
1. Introduction
Polyglutamine diseases including Huntington's disease (HD),
spinocerebellar ataxias (SCAs), dentatorubral and pallidoluysian
atrophy (DRPLA) and spinobulbar muscular atrophy (SBMA)
are autosomal-dominant, adult-onset neurodegenerative disorders.
These diseases are caused by CAG repeat expansions in their caus-
ative genes. The gene products containing expanded polyglu-
tamine form nuclear inclusions in neurons, leading to neuronal
cell dysfunction and finally cell loss.
The causative gene of HD is huntingtin which contains
more than 40 CAG repeats in its exon 1 ( 1 ). The product,
mutant Htt containing expanded polyglutamine repeats forms
nuclear aggregates in neurons in specific regions including the
striatum and cortex, where severe neurodegenerations are
observed ( 2 ). Recent studies have shown that mutant Htt interacts