Cellular ageing, increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice.
Loss-of-function mutations in progranulin (GRN) are associated with frontotemporal lobar degeneration with intraneuronal ubiquitinated protein accumulations composed primarily of hyperphosphorylated TDP-43 (FTLD-TDP). The mechanism by which GRN deficiency causes TDP-43 pathology or neurodegeneration remains elusive. To explore the role of GRN in vivo, we established Grn knockout mice using a targeted genomic recombination approach and Cre-LoxP technology. Constitutive Grn homozygous knockout (Grn(-/-) ) mice were born in an expected Mendelian pattern of inheritance and showed no phenotypic alterations compared to heterozygous (Grn(+/-) ) or wild-type (Wt) littermates until 10 months of age. From then, Grn(-/-) mice showed reduced survival accompanied by significantly increased gliosis and ubiquitin-positive accumulations in the cortex, hippocampus, and subcortical regions. Although phosphorylated TDP-43 could not be detected in the ubiquitinated inclusions, elevated levels of hyperphosphorylated full-length TDP-43 were recovered from detergent-insoluble brain fractions of Grn(-/-) mice. Phosphorylated TDP-43 increased with age and was primarily extracted from the nuclear fraction. Grn(-/-) mice also showed degenerative liver changes and cathepsin D-positive foamy histiocytes within sinusoids, suggesting widespread defects in lysosomal turnover. An increase in insulin-like growth factor (IGF)-1 was observed in Grn(-/-) brains, and increased IGF-1 signalling has been associated with decreased longevity. Our data suggest that progranulin deficiency in mice leads to reduced survival in adulthood and increased cellular ageing accompanied by hyperphosphorylation of TDP-43, and recapitulates key aspects of FTLD-TDP neuropathology.
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.
Hans
H
Wils
Gernot
G
Kleinberger
Sandra
S
Pereson
Jonathan
J
Janssens
Anja
A
Capell
Debby
D
Van Dam
Ivy
I
Cuijt
Geert
G
Joris
Peter P
PP
De Deyn
Christian
C
Haass
Christine
C
Van Broeckhoven
Samir
S
Kumar-Singh
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D015870:Gene Expression; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008099:Liver / Q000473:pathology; D008136:Longevity / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D000077153:Progranulins; D015996:Survival Rate; D025801:Ubiquitin / Q000378:metabolism
D004268:DNA-Binding Proteins; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D025801:Ubiquitin