Deletion of the Huntingtin Polyglutamine Stretch Enhances Neuronal Autophagy and Longevity in Mice. PLoS Genet 6(2): e1000838. doi:10.1371/journal.pgen.1000838 Unraveling the Polyglutamine Puzzle  By Tamara Mauri June 2010  The mutation carried by HD patients is an extension of the normal CAG triplet repeats within the huntingtin (htt) gene, generating a longer-than-normal polyglutamine (polyQ) tract in the htt protein. Although the link between the expanded polyQ tract and disease is not understood, it is known that polyQ length affects the survival of cells in the striatum and cortex, and is associated with cytoplasmic and nuclear aggregates of mutant htt protein. The Study: Researchers have previously developed a HD mouse model carrying 140 CAG repeats in one htt gene (140Q/+ mice) (Menalled et al, J Comp Neurol, 2003, 465:11). These mice display motor and behavioral deficits that recapitulate HD. In the present report, Zheng and co-workers replaced the normal htt gene in the 140Q/+ mouse with a gene completely devoid of the normal, short polyQ region (140Q/Q). Intriguingly, the polyQ deletion restored the motor and behavioral phenotypes of mice to normal. On the cellular level, Q-htt expression in the HD mouse model reduced the number of cytoplasmic htt aggregates. One process that cells use for the degradation of bulk cytoplasmic contents, such as aging organelles and aggregated proteins, is autophagy. Indeed, the authors found increased levels of autophagic markers in Q-htt-expressing mice, and enhanced autophagy upon expression of Q-htt in neuroblastoma cells. This led them to hypothesize that deletion of the polyQ tract in one htt gene results in more efficient autophagic clearance of mutant htt aggregates and phenotypic rescue. How can this be? Huntingtin is a large protein that interacts with numerous other proteins. It has been found in different subcellular loci, where it may act as a scaffold for the correct assembly of molecular partners in time and space. Although it was not tested in this study, it is possible that removal of the polyQ tract could alter the protein-protein interactions contributing to htt’s neuroprotective activity. Also, the decreased mutant htt aggregation and increased autophagy observed upon polyQ deletion are consistent with the possibility that normal htt plays a role in autophagy, and that htt’s polyQ stretch may modulate this function. Significance: Besides providing insight into the function of htt’s polyQ stretch, this work implicates autophagy as a targetable cellular process for treatment: methods to stimulate autophagy may be therapeutic in HD and other neurodegenerative diseases. For a recent report on HD treatment strategies involving new drugs and pathways that upregulate autophagy, see Sarkar and Rubinsztein, FEBS Journal 2008, 275:4263.