Dopaminergic neuron‐specific deletion of p53 gene is neuroprotective in an experimental Parkinson's disease model

Abstract

p53, a stress response gene, is involved in diverse cell death pathways and its activation has been implicated in the pathogenesis of Parkinson's disease (PD). However, whether the neuronal p53 protein plays a direct role in regulating dopaminergic (DA) neuronal cell death is unknown. In this study, in contrast to the global inhibition of p53 function by pharmacological inhibitors and in traditional p53 knock-out (KO) mice, we examined the effect of DA specific p53 gene deletion in DAT-p53KO mice. These DAT-p53KO mice did not exhibit apparent changes in the general structure and neuronal density of DA neurons during late development and in aging. However, in DA-p53KO mice treated with the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), we found that the induction of Bax and PUMA mRNA and protein levels by MPTP were diminished in both striatum and substantia nigra (SN) of these mice. Notably, deletion of the p53 gene in DA neurons significantly reduced dopaminergic neuronal loss in SN, dopaminergic neuronal terminal loss at striatum and, additionally, decreased motor deficits in mice challenged with MPTP. In contrast, there was no difference in astrogliosis between WT and DAT-p53KO mice in response to MPTP treatment. These findings demonstrate a specific contribution of p53 activation in DA neuronal cell death by MPTP challenge. Our results further support the role of programmed cell death mediated by p53 in this animal model of PD and identify Bax, BAD and PUMA genes as downstream targets of p53 in modulating DA neuronal death in the in vivo MPTP-induced PD model.

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

“…Although best known as a tumor suppressor induced by DNA damage, several studies have documented p53 induction in patient tissue and in experimental models of a variety of chronic and acute neurodegenerative disorders (Culmsee and Mattson, 2005), which include Alzheimer's disease (de la Monte et al, 1997; Kitamura et al, 1997), Huntington’s disease (Bae et al, 2005), Parkinson's disease (Duan et al, 2002; Mogi et al, 2007; Qi et al, 2016), ALS (Martin, 2000; Ranganathan and Bowser, 2010) and traumatic brain injury (Yang et al, 2016). Interestingly, our results demonstrate that induction and nuclear accumulation of p53 are not sufficient to drive neurodegeneration in vivo .…”

Dopaminergic Neuron-Specific Deletion of p53 Gene Attenuates Methamphetamine Neurotoxicity

“…The transgenic line Slc6a3 Cre provided the system for the conditional inactivation of p53 in DA neurons in which Cre recombinase is activated by the DA transporter promoter starting around embryonic day 16 (Backman et al, 2006). TRP53 loxP/loxP mice (Jonkers et al, 2001) were crossed with Slc6a3 Cre knock-in mice to obtain the DA neuronal specific p53 KO mice lines, DATcre(WT/+)/TRP53 loxP/loxP (DAT-p53KO) and DATcre(+/−)/TRP53 WT/WT (DAT-p53WT) mice as described in our recent papers (Filichia et al, 2015, Qi et al, 2016). The method for genotyping and characterizing the specific deletion of p53 in DA neurons was also described in a recent study of ours (Qi et al, 2016) and all mice strains in this study were maintained in a C57BL/6 genetic background.…”

“…TRP53 loxP/loxP mice (Jonkers et al, 2001) were crossed with Slc6a3 Cre knock-in mice to obtain the DA neuronal specific p53 KO mice lines, DATcre(WT/+)/TRP53 loxP/loxP (DAT-p53KO) and DATcre(+/−)/TRP53 WT/WT (DAT-p53WT) mice as described in our recent papers (Filichia et al, 2015, Qi et al, 2016). The method for genotyping and characterizing the specific deletion of p53 in DA neurons was also described in a recent study of ours (Qi et al, 2016) and all mice strains in this study were maintained in a C57BL/6 genetic background. For the MA binge exposure (MA binge group), mice were administered binge injections (MA 10 mg/kg, x4, per 2hr, s.c.) and saline was injected as the control vehicle in both WT and KO mice.…”

“…The tumor suppressor gene p53 plays an essential role in the regulation of cell death in DA neurons (Trimmer et al, 1996, Porat and Simantov, 1999, Perier et al, 2007, Qi et al, 2016). The possibility for p53 involvement in MA-induced toxicity is supported by the observations that MA caused marked increases in p53-like immunoreactivity in wild-type mice (Hirata and Cadet, 1997) and that the p53 downstream target genes, BAX and p21, were demonstrated upregulated by MA exposure (Pereira et al, 2006, Astarita et al, 2015).…”

“…To specifically address this, we generated DA neuron-specific p53 gene deletion mice (Qi et al, 2016) and examined the role of p53 in MA neurotoxicity. The focus of our studies was to determine the specific role of DA neuronal p53 in MA mediated neurotoxicity and to identify target genes that are differentially regulated in DA specific p53KO mice subjected to MA binge exposure.…”