O4‐06‐01: Neuropathological characterization of progranulin‐deficient mice: Accelerated lipofuscin accumulation suggests a role for progranulin in successful aging

In the periphery, progranulin is involved in wound repair, inflammation, tumor formation and trophic support. Little is known about the role of progranulin in the CNS; however, roles in development, sexual differentiation and long-term neuronal survival have been suggested. Mutations in the gene encoding progranulin (GRN) cause frontotemporal degeneration with ubiquitin and TDP-43 immunoreactive neuronal inclusions due to haploinsufficiency; however, it is currently unclear how this deficiency leads to neurodegeneration. Using GRN-deficient (-/+ and -/-) mice, we investigated the neuropathological consequences of progranulin deficiency. Histological techniques, immunohistochemistry and electron microscopy (EM) were utilized to compare neuropathological changes in an aged-series of GRN-deficient mice to wild-type controls. GRN-/- mice had reduced viability, since crossbreeding of GRN+/− mice resulted in a lower than expected Mendelian ratio for GRN-/- mice. Premature death of GRN-/- mice that was decreased with improved husbandry suggests increased sensitivity to handling stress. GRN-/- mice had age-associated increase in intra-neuronal ubiquitin-, which was particularly severe in the hippocampus and thalamus, but showed no abnormal TDP-43-immunoreactivity. This corresponded to autofluorescent pigment, which was shown to be lipofuscin by EM. Ubiquitin-positive, lipofuscin in 7-month old GRN-/- mice was equivalent to that observed in 23-month wild-type mice. Although no overt neuronal loss was observed; GRN-/- mice had microgliosis, astrogliosis and tissue vacuolation. Our oldest GRN-/- mouse (23 months) had focal neuronal loss and very severe gliosis. GRN-/+ were histologically unremarkable and equivalent to wild-type littermates. GRN-/- mice have reduced pre-natal viability consistent with the reported role of progranulin in development. Lipofuscin accumulation, a marker of age-associated cellular stress, suggested that GRN-/- mice may have accelerated neuronal aging. A role of progranulin in successful aging is compatible with its suggested role as a trophic factor required for long-term neuronal survival. Microvacuolation and gliosis at younger ages and focal neuronal loss and very severe gliosis in our oldest GRN-/- mouse suggests that progranulin deficiency leads to neurodegeneration in this model. Exposure of GRN-deficient mice to additional non-lethal stressors (e.g., hypoxic) might produce neurodegeneration in GRN-/+ mice, as well as GRN-/- mice at younger ages.