Glucose deprivation regulates the progranulin-sortilin axis in PC12 cells.
Progranulin (PGRN) is a growth factor implicated in several neurodegenerative diseases, such as frontotemporal lobar degeneration. Despite its important role in the central nervous system (CNS), the mechanisms controlling PGRN expression in the CNS are largely unknown. Recent evidence, however, suggested that several stressors, such as hypoxia, acidosis, or oxidative stress, induce PGRN expression. The present study was mainly aimed at determining whether and, if so, how glucose deprivation affects PGRN expression in PC12 cells. Initially, it was found that glucose deprivation gradually inducedPGRNgene expression in PC12 cells. To elucidate the underlying molecular mechanisms, several intracellular signalings that were modified in response to glucose deprivation were examined. Both adenosine monophosphate kinase (AMPK) activation and changes in osmotic pressure, which are modified by extracellular glucose concentration, had no effect onPGRNgene expression; on the other hand, p38 activation in response to glucose deprivation played an important role in inducingPGRNgene expression. It was also found that expression of sortilin, a PGRN receptor implicated in PGRN endocytosis, was dramatically reduced by glucose deprivation. In contrast to glucose-dependent regulation ofPGRNgene expression, AMPK activation played a central role in reducing sortilin expression. Overall, the present study suggests that the PGRN-sortilin axis is modulated by glucose deprivation via two distinct mechanisms. As PGRN is neuroprotective, this system may represent a new neuroprotective mechanism activated by glucose deprivation in the CNS.
Graduate School of Life Sciences Toyo University Oura-gun Gunma Japan.
Ken-Ichi
KI
Kawashima
Graduate School of Life Sciences Toyo University Oura-gun Gunma Japan.
Yuri
Y
Ishiuchi
Department of Applied Biosciences Faculty of Life Sciences Toyo University Oura-gun Gunma Japan.
Miki
M
Konnai
Department of Applied Biosciences Faculty of Life Sciences Toyo University Oura-gun Gunma Japan.
Saori
S
Komatsu
Graduate School of Life Sciences Toyo University Oura-gun Gunma Japan.
Hitoshi
H
Sato
Graduate School of Life SciencesToyo University Oura-gun Gunma Japan; Department of Applied Biosciences Faculty of Life Sciences Toyo University Oura-gun Gunma Japan.
Hideo
H
Kawaguchi
Graduate School of Food and Nutritional Sciences Toyo University Oura-gun Gunma Japan.
Nobumitsu
N
Miyanishi
LBTI UMR CNRS 5305 - University Claude Bernard Lyon I Lyon France.
Jérôme
J
Lamartine
Graduate School of Agricultural and Life Sciences The University of Tokyo Japan.
Masugi
M
Nishihara
Graduate School of Life SciencesToyo University Oura-gun Gunma Japan; Department of Applied Biosciences Faculty of Life Sciences Toyo University Oura-gun Gunma Japan.
Taku
T
Nedachi
PC12 cells; glucose; progranulin; sortilin