Cellular ageing, increased mortality and FTLD‐TDP‐associated neuropathology in progranulin knockout mice

• DOI: 10.1002/path.4043
• Publication Date: 2012-06-25T15:29:57Z
• Authors: Hans Wils; Gernot Kleinberger; Sandra Pereson; Jonathan Janssens; Anja Capell; Debby Van Dam; Ivy Cuijt; Geert Joris; Peter P De Deyn; Christian Haass; Christine Van Bro...; Samir Kumar‐Singh
• Keywords: Frontotemporal lobar degeneration; Hyperphosphorylation; Knockout mouse; Neuropathology; Tauopathy; Proteostasis

Abstract Loss‐of‐function mutations in progranulin ( GRN ) are associated with frontotemporal lobar degeneration intraneuronal ubiquitinated protein accumulations composed primarily of hyperphosphorylated TDP‐43 (FTLD‐TDP). The mechanism by which deficiency causes pathology or neurodegeneration remains elusive. To explore the role vivo , we established Grn knockout mice using a targeted genomic recombination approach and Cre‐LoxP technology. Constitutive homozygous (Grn −/− were born an expected Mendelian pattern inheritance showed no phenotypic alterations compared to heterozygous +/− wild‐type (Wt) littermates until 10 months age. From then, reduced survival accompanied significantly increased gliosis ubiquitin‐positive cortex, hippocampus, subcortical regions. Although phosphorylated could not be detected inclusions, elevated levels full‐length recovered from detergent‐insoluble brain fractions mice. Phosphorylated age was extracted nuclear fraction. also degenerative liver changes cathepsin D‐positive foamy histiocytes within sinusoids, suggesting widespread defects lysosomal turnover. An increase insulin‐like growth factor (IGF)‐1 observed brains, IGF‐1 signalling has been decreased longevity. Our data suggest that leads adulthood cellular ageing hyperphosphorylation TDP‐43, recapitulates key aspects FTLD‐TDP neuropathology. Copyright © 2012 Pathological Society Great Britain Ireland. Published John Wiley & Sons, Ltd.