Abstract
In the current study we present evidence suggesting that PARP-1 regulates neurogenesis and its deficiency may result in schizophrenia-like behavioral deficits in mice. PARP-1 knockout neural stem cells exhibited a marked upregulation of embryonic stem cell phosphatase that can suppress the proliferative signaling of PI3K-Akt and ERK. The suppressed activity of Akt and ERK in the absence of PARP-1 results in the elevation of FOXO1 activity and its downstream target genes p21 and p27, leading to the inhibition of neural stem cell proliferation. Moreover, expression of neurogenic factors and neuronal differentiation were decreased in the PARP-1 knockout neural stem cells whereas glial differentiation was increased. In accordance with the in vitro data, PARP-1 knockout mice exhibited reduced brain weight with enlarged ventricle as well as decreased adult neurogenesis in the hippocampus. Interestingly, PARP-1 knockout mice exhibited schizophrenia-like symptoms such as anxiety, depression, social interaction deficits, cognitive impairments, and prepulse inhibition deficits. Taken together, our results suggest that PARP-1 regulates neurogenesis during development and in adult and its absence may lead to the schizophrenia-like behavioral abnormality in mice.
Highlights
Poly(ADP-ribose) polymerase-1 (PARP-1) is a multifunctional nuclear enzyme that regulates DNA repair, gene expression and cell death by attaching poly(ADPribose) (PAR) on many important regulators of these processes[1]
We present evidence suggesting that PARP-1 promotes neurogenesis by regulating PI3K, Akt, ERK, and FOXO1 signaling via PARP activitydependent regulation of embryonic stem cell phosphatase (ESP) expression
PARP-1-deficient NSCs exhibit defects in proliferation To examine whether PARP-1 is involved in the regulation of neurogenesis, we first performed neurosphere formation assay using PAPR-1 KO NSCs
Summary
Poly(ADP-ribose) polymerase-1 (PARP-1) is a multifunctional nuclear enzyme that regulates DNA repair, gene expression and cell death by attaching poly(ADPribose) (PAR) on many important regulators of these processes[1]. When overactivated by massive DNA damage, PARP-1 can induce cell death by depleting NAD+2. PARP-1 can act as a survival factor under tolerable DNA damage condition by detecting and repairing the damage[3]. PARP-1-deficient cells exhibit higher rate of genomic instability and enhanced susceptibility toward genotoxic insults[1]. PARP-1 has been extensively studied as a target for cancer pharmacotherapy[4]. There have been studies suggesting that PARP-1 is involved in the regulation of cell proliferation.
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