Cellular Senescence and Microglia in Progranulin Deficient Frontotemporal Dementia Pathogenesis

Frontotemporal dementia (FTD) is a neurodegenerative disease that affects patients younger than 65. FTD is characterized by the degeneration of the frontal and temporal lobes, leading to progressive behavioral and/or language problems. FTD is a highly heritable neurodegenerative disorder, with 40-50% of patients having a strong family history. Among familial FTD patients, ∼12% carry dominant mutations in the Progranulin (GRN) gene, which result in nonsense-mediated decay in GRN mRNA and haploinsufficiency of the Progranulin (PGRN) protein. Previous studies show that PGRN deficiency causes aberrant age-dependent microglial activation that preferentially affects the thalamocortical circuit of Grn-/- mice. However, how PGRN loss causes cell senescence remains unknown. By performing β-galactosidase activity tests and immunohistochemistry with the Iba1 antibody in the Grn-/- mouse brain and postmortem human brain tissues from patients with GRN mutations, we showed that cellular senescence is a prominent feature that contributes to the expansion of microglia in 4 to 18 month old Grn-/- mouse brains and in patients with GRN mutations. Specifically, microgliosis and increased β-galactosidase activity were detected in the ventral thalamus of Grn-/- mice. Similar microgliosis and cellular senescence phenotypes can be detected in the microglia in the frontal cortex and thalamus of FTLD-GRN carriers. In conclusion, the results support that cell senescence is key and a highly conserved feature in mouse and human microglia with progranulin deficiency. This phenotype most likely contributes to neurodegeneration in Grn-/- mice and in patients with GRN mutations. The research has been done under the guidance and support of Yu-Hsin Huang and Eric J. Huang at the Huang Lab at the University of California, San Francisco.