TY - JOUR
T1 - Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging
AU - Ahmed, Zeshan
AU - Sheng, Hong
AU - Xu, Ya Fei
AU - Lin, Wen Lang
AU - Innes, Amy E.
AU - Gass, Jennifer
AU - Yu, Xin
AU - Hou, Harold
AU - Chiba, Shuichi
AU - Yamanouchi, Keitaro
AU - Leissring, Malcolm
AU - Petrucelli, Leonard
AU - Nishihara, Masugi
AU - Hutton, Michael L.
AU - McGowan, Eileen
AU - Dickson, Dennis W.
AU - Lewis, Jada
PY - 2010/7
Y1 - 2010/7
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2010.090915
DO - 10.2353/ajpath.2010.090915
M3 - Article
C2 - 20522652
AN - SCOPUS:77954578417
VL - 177
SP - 311
EP - 324
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 1
ER -