Deconstructing the Cellular and Molecular Basis of Polyglutamine Neurodegeneration: A Tale of Two Repeat Diseases

Repeat expansion mutations have emerged as a frequent cause of inherited neurological disorders. One class of repeat expansion mutations involve CAG trinucleotide repeats that encode expanded glutamine tracts in nine different inherited neurodegenerative diseases, including Huntington's disease (HD), X-linked spinal & bulbar muscular atrophy (SBMA), and six forms of spinocerebellar ataxia. In this lecture, I will focus on recent advances in our understanding of two of these polyglutamine disorders - SBMA and HD. Based upon results obtained in variety of model systems, including especially mice and reprogrammed patient stem cells, I will offer novel insights into how motor neurons degenerate in SBMA and why studies of HD have revealed a previously unappreciated essential role for a PPAR transcription factor in neurons, allowing targeted therapy development.