Histopathological analysis of progranulin knockout mice

Abstract

Ubiquitin (Ub)- and p62-positive inclusions are the pathological hallmarks of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). Mutations of progranulin (PGRN) gene result in a reduction of PGRN level and cause FTLD-U. TAR DNA-binding protein 43 (TDP-43) is a major component of inclusions in FTLD-U and ALS. To investigate the relation between the PGRN reduction and the inclusion formation, we histochemically analyzed the brains of PGRN homo knockout (KO), hetero KO and wild type mice at 12 or 24 months of age, using antibodies for TDP-43, Ub and p62. All anti-TDP-43 antibodies used did not stain any abnormal structures in all mice. On the other hand, p62-positive structures were observed in the thalamus and the spinal cord of hetero KO and homo KO mice. The number of these structures was greater in homo KO than in hetero KO, and in 24 months of age than in 12 months of age. These results suggest that PGRN deficiency is not sufficient to cause accumulation of TDP-43, and that the PGRN level is associated with p62 metabolism, which is regulated by autophagy. A reduction of PGRN may result in the dysfunction of autophagy, leading to p62 accumulation.