Neurobiology Select

Neurodegenerative diseases cause profound suffering, and patients are often faced with few therapeutic options. Elucidating new therapeutic avenues requires a better understanding of the aberrant molecular mechanisms that result in death of select neuronal populations. Recent studies use classic cell and molecular biology assays and the latest sequencing technologies to investigate the molecular pathogenesis of different neurodegenerative diseases from the DNA level to the whole organism. Huntington's disease (HD) is a hereditary neurodegenerative disorder in which aberrant expansion of glutamine repeats in the protein huntingtin results in a mutant protein that is prone to forming aggregates. Although mutant huntingtin is cleared by the autophagy pathway, the aggregates accumulate, eventually killing striatal neurons in the brain. Mar-tinez-Vicente et al. (2010) now shed fresh light on the part played by a type of autophagy called macroautophagy in HD pathogenesis. During macroautophagy, regions of cyto-plasm including organelles are engulfed into large double-membraned vesicles called autophagosomes, which then fuse with lysosomes, resulting in degradation of the auto-phagosomes' cytosolic cargo. The authors first looked at embryonic fibroblasts from wild-type mice with normal 18-glutamine-repeat huntingtin and HD mice with mutant 111-glutamine-repeat huntingtin. Although macroautophagy was activated in both cell types in response to serum removal, there was markedly less protein degradation in HD cells compared with wild-type cells. There was also decreased protein degradation after macroautophagy activation in lymphoblasts from HD patients and in striatal neurons from another HD mouse model in which exon 1 of mutant human huntingtin is overexpressed. Using biochemical and morphological assays, the authors then showed that decreased protein degradation in HD cells was not due to a defect in macroautophagy activation or lysosome activity, or decreased expression of autophagy-associated proteins, including Atg4 and beclin-1. But when they compared normal and HD mouse and human cells by electron microscopy, they realized that although autophagosomes formed properly in HD cells, they seemed to be ''empty,'' lacking a normal cytosolic cargo of organelles and polyubiquitinated proteins. The authors propose that a decreased ability to sequester cytosolic components in HD cells could slow degradation of unwanted organelles and proteins contributing to neuronal toxicity in HD. But how could mutant huntingtin be involved in this macroautophagy defect? The authors discovered that mutant huntingtin interacted abnormally with a key cargo recognition molecule (p62), suggesting that it may disrupt cargo recognition by autophagosomes. It is also possible that mutant huntingtin binds directly to cargo proteins, preventing their engulfment …