Proteinopathy and lysosomal dysfunction in Sanfilippo disease: linking mechanisms and role in neuroinflammatory astrocytes

Sanfilippo syndrome is an inherited rare disease characterized by a severe brain involvement. Unfortunately, to date, there are no effective therapies for the treatment of brain pathology in Sanfilippo patients. Autophagy is a degradative process dependent on functional lysosomes, by which macromolecules are disposed by cells. Autophagy plays a crucial role in the clearance of toxic protein aggregates. In fact, when autophagy does not work properly, proteins, which are propense to aggregate form toxic deposits in the cells. On the other hand, protein aggregation itself may affect autophagy function, thus generating a vicious cycle. We have demonstrated that such detrimental interplay between autophagy dysfunction and protein aggregation drives neurodegeneration in Sanfilippo disease. While these processes in the brain have been mostly studied in neurons, their contribute in other brain cells such as astrocytes to neurodegeneration represents an underexplored field. Moreover, the mechanisms linking protein aggregation to autophagy dysfunction remain partially clarified
Here we want:

1. To investigate whether protein aggregation and autophagy defects contribute to the generation of reactive astrocytes, a key event triggering neuroinflammatory process in Sanfilippo disease, as well as in other neurodegenerative conditions.
2. To study the impact of protein aggregation on lysosome membrane organization, focusing on the interaction of lysosomal membrane with endoplasmic reticulum. We hypothesize that altering such interaction may cause lysosomal dynamic impairment and autophagy defects observed in Sanfilippo disease

The results generated by this research proposal may identify new disease mechanism, thus open new avenues for the treatment of Sanfilippo syndrome.