Disease’ mechanisms and pharmacological targeting of behavioral symptoms in Sanfilippo Syndrome

Mucopolysaccharidosis type IIIA or Sanfilippo A disease is a neurodegenerative inherited lysosomal storage disorder (LSD) caused by deficiency of a sulfatase enzyme, the Sulfamidase, leading to the heparan sulfate (HS) accumulation and central nervous system (CNS) abnormalities. Recent findings have pointed out to a defective autophagosome-lysosome fusion and supported a direct toxic mechanism of Glycosaminoglycans (GAGs) accumulation in the pathogenesis of the MPS-IIIA disease. Hence, it is becoming clear that new studies are required for a deep knowledge of the MPS-IIIA pathogenesis and to develop therapeutic strategies aimed at alleviating both pathological HS and GAGs accumulation through degradation of these compounds. Based on this, our main research goal is to achieve a deep understanding of the molecular pathway controlling autophagy in the CNS and to translate cell clearance discoveries into novel therapeutic strategies for the treatments of MPS-IIIA. Towards this aim, after identification of the Ezrin gene as lysosomal-autophagic repressor, we are now characterizing its role in the regulation of autophagy. The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from July 2016 until last budget year, calculated based on the size of the research group.