PGRN deficiency exacerbates, whereas a brain penetrant PGRN derivative protects, <i>GBA1</i> mutation-associated pathologies and diseases.

Abstract

Mutations in <i>GBA1</i>, encoding glucocerebrosidase (GCase), cause Gaucher disease (GD) and are also genetic risks in developing Parkinson's disease (PD). Currently, the approved therapies are only effective for directly treating visceral symptoms, but not for primary neuronopathic involvement in GD (nGD). Progranulin (PGRN), encoded by <i>GRN</i>, is a novel modifier of GCase, but the impact of PGRN in <i>GBA1</i> mutation-associated pathologies in vivo remains unknown. Herein, <i>Grn<b>^-/-</b></i> mice crossed into <i>Gba</i>^9v/9v mice, a <i>Gba1</i> mutant line homozygous for the <i>Gba1</i> D409V mutation, generating <i>Grn<b>^-/-</b></i><i>Gba</i>^9v/9v (PG9V) mice. PG9V mice exhibited neurobehavioral deficits, early onset, and more severe GD phenotypes compared to <i>Grn<b>^-/-</b></i> and <i>Gba</i>^9v/9v mice. Moreover, PG9V mice also displayed PD-like phenotype. Mechanistic analysis revealed that PGRN deficiency caused severe neuroinflammation with microgliosis and astrogliosis, along with impaired autophagy associated with the <i>Gba1</i> mutation. A PGRN-derived peptide, termed ND7, ameliorated the disease phenotype in GD patient fibroblasts ex vivo<i>.</i> Unexpectedly, ND7 penetrated the blood-brain barrier (BBB) and effectively ameliorated the nGD manifestations and PD pathology in <i>Gba</i>^9v/null and PG9V mice. Collectively, this study not only provides the first line of in vivo but also ex vivo evidence demonstrating the crucial role of PGRN in <i>GBA1/Gba1</i> mutation-related pathologies, as well as a clinically relevant mouse model for mechanistic and potential therapeutics studies for nGD and PD. Importantly, a BBB penetrant PGRN-derived biologic was developed that may provide treatment for rare lysosomal storage diseases and common neurodegenerative disorders, particularly nGD and PD.