In my first contribution to the Cross-Border Biotech Blog’s Friday Science Review we have a promising advance in the treatment of Huntington’s disease by an international collaboration led by researchers from the Department of Pharmacology at the University of Alberta and another look at the surprisingly small number of critical genes in organisms by the Fraser lab at the University of Toronto.
A promising new avenue for Huntington’s Disease
The autosomal dominant genetic disorder Huntington’s disease (HD) is caused by the expansion of the CAG codon in the Huntingtin gene and the resulting inclusion of an abnormally long poly-glutamine stretch in the Huntingtin (Htt) protein. The expanded poly-glutamine stretch results in misfolding of the Htt protein and the formation of aggregates that are deposited as inclusion bodies within cells. As Htt protein is most highly expressed in neuronal cells, the aggregates lead to impaired neuronal transmission and ultimately to neuronal death, resulting in the loss of muscle coordination, cognitive impairment and psychiatric problems that are characteristic of HD.
Current treatments for HD are palliative in nature only, however, the paper by Di Pardo et al, published in PNAS, aimed to address the molecular mechanisms of HD by intraventricular infusion of the ganglioside GM1 – for those of us that like to picture molecules, GM1 is a glycosphingolipid with a headgroup attached sialic acid. GM1 levels have previously been shown to be reduced in HD animal models and post mortem HD patient brain samples. In this study, they show that infusion of GM1 reduces Htt toxicity and restores normal motor function in symptomatic HD mice models. GM1 appeared to exert its effect, by inducing an increase in DARPP-32 levels and phosphorylation, as well as by inducing the phosphorylation of the Htt protein at specific serine residues that reduce Htt toxicity.
While there is the chance that the rather invasive GM1 approach itself might represent a therapy, at the least, these results suggest new therapeutic pathways to research and target for the treatment of HD.
Eukaryotic genes: Necessary, but not required?
Previous studies in a range of model organisms have presented us with something of a paradox: eukaryotic genomes are highly conserved indicating that most genes are functionally important, yet only a minority of genes have detectable loss-of-function phenotypes. Models explaining this paradox range from suggestions that genetic networks have evolved to be robust and resistant to individual mutations, to suggestions that the targeted genes are essential, but just don’t happen to be required in the particular conditions used in the experiments.
The Fraser lab at the Donnelly Centre of the University of Toronto has helped resolve this paradox by showing in last weeks issue of Cell that, in fact, the majority of genes in C. elegans, if individually suppressed by RNA mediated interference, result in lower multi-generational fitness compared to wild-type. This result challenges the model that genetic networks are robust and instead suggests that the loss of most genes results in phenotypes that were too subtle to have been detected by previous assays. The complex interactions and subtle phenotypes, that manifested as decreased fitness, emphasizes that the development of a systems level understanding of gene function will be increasingly important to understand the molecular basis of diseases.
- SKI-1 and Furin Generate Multiple RGMa Fragments that Regulate Axonal Growth. Developmental Cell. Toronto Western Research Institute ♦ University of Toronto
- Negative Supercoiling Creates Single-Stranded Patches of DNA That Are Substrates for AID-Mediated Mutagenesis. PLoS Genetics. University of Toronto
- Genetic variation in cell death genes and risk of non-hodgkin lymphoma. PLoS One. Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
- Caffeic Acid phenethyl ester and its amide analogue are potent inhibitors of leukotriene biosynthesis in human polymorphonuclear leukocytes. PLoS One. Université de Moncton