The molecular mechanisms of neurodegeneration...

The Fanto Lab studies the molecular mechanisms of neurodegeneration by polyglutamines, mainly using Drosophila as a model system. In our approaches, disease modelling is guided by the knowledge of the endogenous fly background and is always paralleled by the study of the normal processes in which the corresponding fly genes are involved.

The main research line in the lab is concerned with Atrophins, a family of transcriptional co-factors with several additional roles and implicated in many cellular and developmental processes. Atrophin-1 in humans is responsible for the polyglutammine disease Dentatorubropallydoluisian atrophy (DRPLA). The fly orthologue atro is involved in several processes from embryo segmentation to the establishment of planar cell polarity.

As for all other diseases of the polyglutamine family the precise mechanisms through which neurodegeneration and the neurological manifestations arise are not clear. To address these issues we have generated several Drosophila models for DRPLA by expressing wt and mutated forms of human Atrophin-1 and Drosophila Atro. Our strategy is deliberately multimodel in the attempt of minimising false positives arising from the peculiarity of each model.

Autophagy regulation

Our analysis has revealed that cellular degeneration happens via impairment of the autophagy flux, with a block in clearance of autophagic vacuole after their fusion with lysosomes. This is different from other polyglutamine diseases and suggests lysosomal dysfunction as a key component of DRPLA.

Transcriptional alterations

To understand how this form of neurodegeneration arises we have set up genome wide functional genomic assays. has been proposed that polyQ diseases are transcriptionopathies, in which toxicity first arises from large scale alterations of transcription, and the functional role of Atrophins as transcriptional co-factors further suggest the importance of transcriptional mechanisms. We have monitored by microarrays transcriptional alterations due to polyQ Atrophin expression through an inducible system in the Drosophila retina, a dispensable part of the fly nervous system widely used in polyQ modelling.

Neuronal homeostasis and autophagy regulation by the Hippo pathway

We have established that the fat tumour suppressor gene mediates neurodegeneration induced by the polyglutamine protein Atrophin via deregulation of autophagy. Polyglutamine Atrophins induce autophagic neurodegeneration with lysosomal blockage and repress fat transcription. Fat is known to interact with Atrophin to regulate planar cell polarity, however it protects from autophagic degeneration and Atrophin toxicity through the Hippo tumour suppressor pathway. data thus provide a crucial insight into the specific mechanism of a polyglutamine disease and reveal an unexpected neuroprotective role of Fat and its growth control pathway in the regulation of autophagy and cellular homeostasis.

Glial toxicity as a non autonomous component in DRPLA

Finally we have identified a key role of glial cells in mediating toxicity at the organismal level and we are currently investigating non autonomous mechanisms of toxicity in the fly nervous system.