PROJECT ABSTRACT Mucopolysaccharidosis IIIA (MPS IIIA) is a devastating neurodevelopmental disorder. It is insidious in that early neurologic development is often normal. This normal early development is typically followed by plateauing in ascertainment of new skills followed by regression to a vegetative state and early death, often in the second decade of life. Although there are now ongoing clinical trials of disease modifying therapies, none are currently approved. All of these candidate therapies must overcome the blood-brain barrier for the missing enzyme, Sulfamidase, in MPS IIIA to enter neurons and degrade glycosaminoglycans (GAGs), the storage material that accumulates. The therapies currently being tested, most prominently viral-based gene replacement therapy, suffer from a limited number of neurons that can be infected. Thus, even with cross- correction between neighboring neurons, not all neurons receive an adequate quantity of Sulfamidase to prevent their neurodegeneration. We hypothesize that increasing the stability of Sulfamidase will allow it to accumulate in more neurons, slowing neurodegeneration and improving symptoms in patients with MPS IIIA. We will test this hypothesis by 1) performing a cell-based genome-wide screen to identify proteins which promote Sulfamidase degradation 2) identifying inhibition of which of these proteins increases abundance of endogenous Sulfamidase and 3) determining which of these degradation-promoting proteins directly interact with Sulfamidase. Through these aims, we will identify new therapeutic entry points that can be combined with developing gene-replacement therapies for a dual therapeutic approach for this devastating disorder.