Abstract
Forebrain glial cells - ependymal cells and astrocytes -acquire upon injury- a “reactive” phenotype associated with parvalbumin (PV) upregulation. Since free radicals, e.g. reactive oxygen species (ROS) play a role in the pathogenesis of multiple sclerosis, and that PV-upregulation in glial cells is inversely correlated with the level of oxidative stress, we hypothesized that PV-upregulation might also protect oligodendrocytes by decreasing ROS production. Lentiviral transduction techniques allowed for PV overexpression in CG4 oligodendrocyte progenitor cells (OPCs). Depending on the growth medium CG4 cells can be maintained in an OPC-like state, or induced to differentiate into an oligodendrocyte (OLG)-like phenotype. While increased levels of PV had no effect on cell proliferation and invasiveness in vitro, PV decreased the mitochondria volume in CG4 cell bodies, as well as the mitochondrial density in CG4 processes in both OPC-like and OLG-like states. In line with the PV-induced global decrease in mitochondrial volume, elevated PV levels reduced transcript levels of mitochondrial transcription factors involved in mitochondria biogenesis. In differentiated PV-overexpressing CG4 cells with a decreased mitochondrial volume, UV-induced ROS production was lower than in control CG4 cells hinting towards a possible role of PV in counteracting oxidative stress. Unexpectedly, PV also decreased the length of processes in undifferentiated CG4 cells and moreover diminished branching of differentiated CG4 cell processes, strongly correlated with the decreased density of mitochondria in CG4 cell processes. Thus besides conferring a protective role against oxidative stress, PV in a cell autonomous fashion additionally affects process’ growth and branching in CG4 cells.
Highlights
Forebrain glial cells - ependymal cells and astrocytes -acquire upon injury- a “reactive” phenotype associated with parvalbumin (PV) upregulation
A positive but rather weak signal in the semi-quantitative reverse transcription PCR amplification (RT-PCR) was obtained after 30 cycles
Since endogenous PV levels in C-CG4 cells were below the detection limit for Western blot analyses and no striking differences were observed between shPV- and either C- or GFP-CG4 cells, further experiments were essentially carried out with PV-overexpressing PV-CG4 cells and compared to either C-CG4 or GFP-CG4 cells, the latter serving as a control to possibly detect changes caused by LV transduction
Summary
Forebrain glial cells - ependymal cells and astrocytes -acquire upon injury- a “reactive” phenotype associated with parvalbumin (PV) upregulation. E.g. reactive oxygen species (ROS) play a role in the pathogenesis of multiple sclerosis, and that PV-upregulation in glial cells is inversely correlated with the level of oxidative stress, we hypothesized that PV-upregulation might protect oligodendrocytes by decreasing ROS production. Oligodendrocytes (OLGs) are glial cells with diverse functions in the vertebrate central nervous system (CNS), one crucial being the myelination of long projection axons[1]. Oligodendrocytes are especially vulnerable to oxidative stress, hypoxia, excitatory amino acids, activation of apoptotic pathways, and deprivation of neurotrophic factors[10] They are more sensitive to hypoxic conditions than astrocytes, microglia or endothelial cells, and they are as sensitive to ischemia as neurons[11]. We postulated that injury-induced PV-upregulation in other glial cells might protect against oxidative stress and promote regeneration, and that glial PV-upregulation might occur upon diverse inflammatory processes that involve NF-κB signaling and responses to oxidative stress, such as those observed during the pathogenesis of MS
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