CELLLULAR AND MOLECULAR SPECIFICITY OF POLYGLUTAMINE ATROPHIN TOXICITY

Several dominant neurodegenerative diseases are part of the so called polyglutamine (polyQ) syndromes which share the same molecular origin and some clinical and cellular features although the genes that cause the diseases are different and in principle unrelated. To investigate the molecular mechanisms of these syndromes it is useful to generate animal models in which specific hypothesis can be tested. We have modelled one of the polyQ diseases, dentatorubropallidoluysian atrophy (DRPLA), in the fruitfly Drosophila melanogaster which has proved to be a good model also for other polyQ diseases. We have analysed neurodegeneration in the photoreceptor neurones and found it to happen through the deregulation of the cellular process of autophagy, in which the cells degrades faulty organelles to recycle simple components. Through analysis of the genes whose transcription is altered we have concluded that the neurones loose their differentiated state and stimulate processes normally found in proliferating cells and cancer. The outcome is however not cancer but the degeneration of tyhe cell and we propose to investigate further into this mechanism. We have also observed a shorthening in the lifespan of the fruitflies when the gene resposible for DRPLA is expressed in glial cells. Glial cells are non-neuronal cell that entertain a complex and supportive relationship with neurones and their importance has been demonstrated in other neurodegenerative diseases. We have also established that the effect in the glia is not limited to DRPLA but may represent a feature that is common to several polyQ ataxias. We propose to use our fly models to figure out the role of glia in the disease by investigating specific hypothesis and by conducting an unbiased genetic screen to identify what genes in flies are involved in regulating glial toxicity by polyQ genes. These studies have the potential to identify a new important component in the pathology of polyQ diseases.