Cellular ageing, increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice.
J Pathol
; 228(1): 67-76, 2012 Sep.
Article
em En
| MEDLINE
| ID: mdl-22733568
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Senescência Celular
/
Peptídeos e Proteínas de Sinalização Intercelular
/
Proteínas de Ligação a DNA
/
Degeneração Lobar Frontotemporal
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
J Pathol
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Bélgica