Polyglutamine Expansion Diseases Research Articles

Toward an understanding of polyglutamine neurodegeneration.

Polyglutamine expansion is now recognized to be a major cause of inherited human neurodegenerative disease. The polyglutamine expansion diseases identified so far are slowly progressive disorders in which distinct yet overlapping brain regions are selectively vulnerable to degeneration. Despite their clinical differences these diseases likely share a common pathogenic mechanism, occurring at the protein level and centered on an abnormal conformation of expanded polyglutamine in the respective disease proteins. Recently there has been remarkable progress in our understanding of polyglutamine disease, but still there are many unanswered questions. In this review, I first outline some of the shared features of polyglutamine diseases and then discuss several issues relevant to an understanding of pathogenesis, paying particular attention to possible mechanisms of neurotoxicity.

Regulation of expanded polyglutamine protein aggregation and nuclear localization by the glucocorticoid receptor.

Spinobulbar muscular atrophy and Huntington's disease are caused by polyglutamine expansion in the androgen receptor and huntingtin, respectively, and their pathogenesis has been associated with abnormal nuclear localization and aggregation of truncated forms of these proteins. Here we show, in diverse cell types, that glucocorticoids can up- or down-modulate aggregation and nuclear localization of expanded polyglutamine polypeptides derived from the androgen receptor and huntingtin through specific regulation of gene expression. Wild-type glucocorticoid receptor (GR), as well as C-terminal deletion derivatives, suppressed the aggregation and nuclear localization of these polypeptides, whereas mutations within the DNA binding domain and N terminus of GR abolished this activity. Surprisingly, deletion of a transcriptional regulatory domain within the GR N terminus markedly increased aggregation and nuclear localization of the expanded polyglutamine proteins. Thus, aggregation and nuclear localization of expanded polyglutamine proteins are regulated cellular processes that can be modulated by a well-characterized transcriptional regulator, the GR. Our findings suggest approaches to study the molecular pathogenesis and selective neuronal degeneration of polyglutamine expansion diseases.

Androgen receptor mutation in Kennedy's disease.

Kennedy's disease is an X-linked form of motor neuron disease caused by an expanded polyglutamine repeat in the androgen receptor. While the expansion mutation causes some loss of transcriptional activity by the androgen receptor, the predominant effect of expansion is probably a toxic gain of function, similar to the mechanism of other polyglutamine expansion diseases. Features of the neurodegenerative phenotype of Kennedy's disease have now been reproduced in transgenic animals and neuronal cell culture. Nuclear inclusions of mutant androgen receptor protein are found in these model systems and in autopsy samples from patients with Kennedy's disease.

Pathological mechanisms in Huntington's disease and other polyglutamine expansion diseases.

HD is an autosomal dominant neurodegenerative disorder characterized by involuntary movements, cognitive impairment progressing to dementia, and mood disturbances. The brains of patients show extensive neuronal loss in the striatum, and the cerebral cortex is also affected. The genetic defect causing HD is an expansion of a CAG repeat encoding a polyglutamine stretch in the target protein, named huntingtin. The age of onset of HD is inversely correlated with the size of the expansion. Polyglutamine expansion represents a novel cause of neurodegeneration, which has been shown to be responsible for seven other inherited disorders. The polyglutamine expansion confers a gain of toxic property to the mutated target proteins. Molecular and cellular studies of the brains of patients and of mice models of polyglutamine expansion diseases have led to the identification of abnormal intracellular inclusions representing aggregation of the mutated protein. However, the mechanism whereby such polyglutamine expansion leads to selective neuronal dysfunction and death is still puzzling.

Polyglutamine expansion and Huntington's disease.

Polyglutamine expansion and Huntington's disease.

Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats

Two forms of the neurodegenerative disorder spinocerebellar ataxia are known to be caused by the expansion of a CAG (polyglutamine) trinucleotide repeat. By screening cDNA expression libraries, using an antibody specific for polyglutamine repeats, we identified six novel genes containing CAG stretches. One of them is mutated in patients with spinocerebellar ataxia linked to chromosome 12q (SCA2). This gene shows ubiquitous expression and encodes a protein of unknown function. Normal SCA2 alleles (17 to 29 CAG repeats) contain one to three CAAs in the repeat. Mutated alleles (37 to 50 repeats) appear particularly unstable, upon both paternal and maternal transmissions. The sequence of three of them revealed pure CAG stretches. The steep inverse correlation between age of onset and CAG number suggests a higher sensitivity to polyglutamine length than in the other polyglutamine expansion diseases.