Pathogenesis of Polyglutamine Diseases

Abstract

Abstract Polyglutamine (polyQ) diseases are neurodegenerative disorders caused by expansion in specific genes of a trinucleotide repeat, cytosine–adenine–guanine (CAG), which encodes glutamine. In 1991, CAG repeat expansion in the androgen receptor was linked to spinal and bulbar muscular atrophy (SBMA), thus indicating for the first time a causative role of polyQ expansion in neurodegenerative disorders. Subsequently, polyQ expansions in eight other genes were shown to be responsible for different neurodegenerative diseases, including Huntington disease, dentatorubral‐pallidoluysian atrophy and six types of spinocerebellar ataxia. PolyQ diseases share several features, such as the phenomenon of genetic anticipation, and that to be late‐onset and progressive disorders. Despite these and other common features, specific populations of neurons are vulnerable in each disease. Approximately 20 years after the discovery of expanded polyQ as a leading cause of neurodegeneration, why selective neuronal populations degenerate in each disorder is still an enigma. Key Concepts: Polyglutamine diseases are a family of late onset, genetically inherited neurodegenerative disorders. Polyglutamine diseases are caused by expansion of the CAG trinucleotide repeat encoding glutamine in nine different genes. Expansion of polyglutamine confers a novel, toxic gain of function to the mutant protein. The length of the polyglutamine tract correlates with disease onset and dictates disease severity. Polyglutamine proteins are ubiquitous. None the less, expansion of polyglutamine tracts causes selective neuronal dysfunction and degeneration. Specific populations of neurons degenerate in each polyglutamine disease, giving rise to different clinical disease manifestations.