Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging

Zeshan Ahmed, Hong Sheng, Ya Fei Xu, Wen Lang Lin, Amy E. Innes, Jennifer Gass, Xin Yu, Harold Hou, Shuichi Chiba, Keitaro Yamanouchi, Malcolm Leissring, Leonard Petrucelli, Masugi Nishihara, Michael L. Hutton, Eileen McGowan, Dennis W. Dickson, Jada Lewis

Research output: Contribution to journalArticlepeer-review

172 Scopus citations

Abstract

Progranulin (PGRN) is involved in wound repair, inflammation, and tumor formation, but its function in the central nervous system is unknown. Roles in development, sexual differentiation, and long-term neuronal survival have been suggested. Mutations in the GRN gene resulting in partial loss of the encoded PGRN protein cause frontotemporal lobar degeneration with ubiquitin immunoreactive inclusions. We sought to understand the neuropathological consequences of loss of PGRN function throughout the lifespan of GRN-deficient (-/+ and -/-) mice. An aged series of GRN-deficient and wild-type mice were compared by histology, immunohistochemistry, and electron microscopy. Although GRN-deficient mice were viable, GRN-/- mice were produced at lower than predicted frequency. Neuropathologically, GRN -/+ were indistinguishable from controls; however, GRN-/- mice developed age-associated, abnormal intraneuronal ubiquitin-positive autofluorescent lipofuscin. Lipofuscin was noted in aged GRN+/+ mice at levels comparable with those of young GRN-/- mice. GRN -/- mice developed microgliosis, astrogliosis, and tissue vacuolation, with focal neuronal loss and severe gliosis apparent in the oldest GRN-/- mice. Although no overt frontotemporal lobar degeneration with ubiquitin immunoreactive inclusions type- or TAR DNA binding protein-43-positive lesions were observed, robust lipofuscinosis and ubiquitination in GRN-/- mice is strikingly similar to changes associated with aging and cellular decline in humans and animal models. Our data suggests that PGRN plays a key role in maintaining neuronal function during aging and supports the notion that PGRN is a trophic factor essential for long-term neuronal survival.

Original languageEnglish (US)
Pages (from-to)311-324
Number of pages14
JournalAmerican Journal of Pathology
Volume177
Issue number1
DOIs
StatePublished - Jul 2010

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Fingerprint Dive into the research topics of 'Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging'. Together they form a unique fingerprint.

Cite this