Pro-cathepsin D, Prosaposin, and Progranulin: Lysosomal Networks in Parkinsonism

HighlightsMutations in GBA1, the gene encoding glucocerebrosidase (GCase), confer an increased risk of parkinsonism, directing attention to lysosomal pathways and proteins in Parkinson pathogenesis.Other lysosomal proteins functioning at the acidic lysosomal pH influence GCase function and/or α-synuclein clearance.Three multifunctional proteins (the PPPN): the protease procathepsin D, the pre-activator prosaposin, and the lysosomal biogenesis protein progranulin, along with their respective transporters, are all interconnected. Their interdependency creates potential feedback mechanisms to protect and support cells under stress.The interactions between the PPPN proteins directly impact GCase activity and α-synuclein degradation and lead to the identification of new risk factors and therapeutic targets for Parkinson disease.AbstractMutations in GBA1, the gene encoding the lysosomal hydrolase glucocerebrosidase (GCase), are a risk factor for parkinsonism. Pursuing the potential mechanisms underlying this risk in aging neurons, we propose a new network uniting three major lysosomal proteins: (i) cathepsin D (CTSD), which plays a major role in α-synuclein (SNCA) degradation and prosaposin (PSAP) cleavage; (ii) PSAP, essential for GCase activation and progranulin (PGRN) transport; and (iii) PGRN, impacting lysosomal biogenesis, PSAP trafficking, and CTSD maturation. We hypothesize that alterations to this network and associated receptors modify lysosomal function and subsequently impact both SNCA degradation and GCase activity. By exploring the interactions between this protein trio and each of their respective transporters and receptors, we may identify secondary risk factors that provide insight into the relationship between these lysosomal proteins, GCase, and SNCA, and reveal novel therapeutic targets.