Gene expression profiling of brain tissue from neuronopathic Gaucher disease mouse model of PG9VN, PG9V and wild type mice

To understand the intrinsic link between PGRN and Gba D409V mutation dosage in regulating lysosomal function and disease pathogenesis, we generated nGD model of GbaD409V/D409V and loss of PGRN (Grn-/-), termed PG9V that displayed typical neuronopathic GD (nGD). With decreasing the dose of Gba D409V, i.e., D409V/Null, in Grn KO mice (Grn-/-;GbaD409V/Null, PG9VN) led to much earlier onset and more severe neurodegenerative nGD than PG9V mice. To explore the correlation between the Gba mutation dosage and both neurodegeneration and inflammation, as well as to attain molecular insights into the underlying brain pathology in PG9VN mice, we performed bulk RNA sequencing analysis on 7.5-month-old PG9VN, PG9V and WT brain tissues containing thalamus, hypothalamus and midbrain, the predominant regions displaying the neuroinflammation and neurodegeneration. Gene Ontology (GO) analysis classified similar molecular pathways were altered in both PG9V and PG9VN mice. The heightened dysregulation of these pathways may be a contributing factor to the more severe disease phenotypes observed in PG9VN mice. This dysregulation appears to be controlled by a threshold effect related to Gba dosage.