Neurodegeneration in CAG Triplet Repeat Diseases, from Molecular Pathogenesis to Rational Therapeutics

The family of CAG triplet repeat diseases includes Huntington's disease, several forms of Spino-Cerebellar Ataxia, and rarer diseases such as Dentato-Rubral and Pallido-Luysian Atrophy and Spinal and Bulbar Muscular Atrophy. Now, over 25 years since the initial discovery of the causative genes, disease-modifying therapeutics are coming to the clinic, with several forms of Anti-Sense Oligonucleotide and RNA interference therapy in human clinical trials. While this represents a potential triumph of modern medical research and rational drug design, establishment of efficacy will require well-designed clinical trials. Furthermore, the daunting problems of delivery of large-molecule therapeutics, for a lifetime, make it imperative to continue to pursue basic science investigations, in search of therapeutic targets for small molecules or other approaches. Answers to many fundamental questions are still uncertain. To what extent is pathogenesis via RNA or protein or both? To the degree that protein is responsible, what are the conformations of the wild type and mutant proteins? How does conformational change take place, and how do different conformations interact with different cellular constituents? What post-translational modifications influence toxicity? Why is there selective neuronal vulnerability, with overlapping but distinct patterns for each disease? How does pathology spread within the brain? What is the role of modifier genes? What are the relationships between cell vulnerability and cell compensation? What are the roles of glia vs neurons vs other cells? What are the molecular and cellular pathways of pathogenesis, and are pathways shared among the diseases? Most important, what will be the most promising therapeutic targets, especially for early stage intervention? The meeting will convey current concepts and controversies, with the latest data addressing them, and promote consideration of mechanistic explanations across diseases. There will be ample time for probing critical discussion, and opportunities for young investigators to present on important topics, including talks selected from submitted poster abstracts, which will be integrated into all sessions.