PGRN deficiency exacerbates, whereas a brain penetrant PGRN derivative protects, GBA1 mutation-associated pathologies and diseases

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 1; p. e2210442120
• Main Authors: Zhao, Xiangli, Lin, Yi, Liou, Benjamin, Fu, Wenyu, Jian, Jinlong, Fannie, Venette, Zhang, Wujuan, Setchell, Kenneth D R, Grabowski, Gregory A, Sun, Ying, Liu, Chuan-Ju
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03-01-2023
• Subjects: Animals; Autophagy; Biological Sciences; Blood-brain barrier; Brain - metabolism; Fibroblasts; Gaucher Disease - genetics; Gaucher's disease; Gliosis; Glucosylceramidase; Glucosylceramidase - genetics; Glucosylceramidase - metabolism; In vivo methods and tests; Inflammation; Lysosomal storage diseases; Lysosomes - metabolism; Mice; Mice, Knockout; Movement disorders; Mutation; Neurodegenerative diseases; Parkinson Disease - genetics; Parkinson's disease; Phenotypes; Progranulins - genetics; Signs and symptoms; progranulin; Gaucher disease; progranulin-derived biologic; Parkinson’s disease; GBA1 mutation
• DOI: 10.1073/pnas.2210442120
• EISSN: 1091-6490
• ISSN: 0027-8424

Mutations in
, 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
, is a novel modifier of GCase, but the impact of PGRN in
mutation-associated pathologies in vivo remains unknown. Herein,
mice crossed into
mice, a
mutant line homozygous for the
D409V mutation, generating
(PG9V) mice. PG9V mice exhibited neurobehavioral deficits, early onset, and more severe GD phenotypes compared to
and
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
mutation. A PGRN-derived peptide, termed ND7, ameliorated the disease phenotype in GD patient fibroblasts ex vivo
Unexpectedly, ND7 penetrated the blood-brain barrier (BBB) and effectively ameliorated the nGD manifestations and PD pathology in
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
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.