Understanding the interplay between amyloid aggregation and autophagy dysfunction in the neurodegenerative processes in Sanfilippo Syndrome

Autophagy is a degradative process by which macromolecules are disposed by cells. Autophagy requires functional lysosomes to work. In fact, the material to be degraded is engulfed into vesicles called autophagosomes, which fuse with the lysosomes whose enzymes allow degradation. In the Sanfilippo syndrome the autophagic process is impaired as the autophagosomes cannot fuse with the lysosomes. This dysfunction triggers the neurodegenerative processes observed in Sanfilippo syndrome. We have recently shown that one of the mechanisms underlying this dysfunction is caused by abnormal accumulation of amyloid proteins, such as alpha-synuclein. This accumulation occurs in close proximity to the lysosomes, thus preventing them from being transported for fuse with the autophagosomes. When a mouse model of Sanfilippo A is treated with an amyloid protein aggregation inhibitor, autophagy is efficiently re-activated and neurodegenerative processes prevented. How amyloid aggregation impair the transport of lysosomes and thus the completion of autophagy is unclear. In this research proposal we want to understand these mechanisms, testing the hypothesis that alpha-synuclein, the main component of amyloid deposits, directly interacts with the membrane of lysosomes causing their abnormal clustering, which in turns reduces their availability for autophagosome fusion. To test this hypothesis, we will work both in a "cell-free" system (i.e. reconstituted in vitro) and in primary neurons derived from Sanfilippo A mice. The results generated by this research proposal could open new avenues for the treatment of Sanfilippo syndrome.