p53 is Present in Synapses Where it Mediates Mitochondrial Dysfunction and Synaptic Degeneration in Response to DNA Damage, and Oxidative and Excitotoxic Insults

Abstract

A form of programmed cell-death called apoptosis occurs in neurons during development of the nervous system, and may also occur in a variety of neuropathological conditions. Here we present evidence obtained in studies of adult mice and neuronal cell cultures showing that p53 protein is present in synapses where its level and amount of phosphorylation are increased following exposure of the cells to the DNA-damaging agent etoposide. We also show that levels of active p53 increase in isolated cortical synaptosomes exposed to oxidative and excitotoxic insults. Increased levels of p53 also precede loss of synapsin I immunoreactive terminals in cultured hippocampal neurons exposed to etoposide. Synaptosomes from p53-deficient mice exhibit increased resistance to oxidative and excitotoxic insults as indicated by stabilization of mitochondrial membrane potential and decreased production of reactive oxygen species. Finally, we show that a synthetic inhibitor of p53 (PFT-alpha) protects synaptosomes from wild-type mice against oxidative and excitotoxic injuries, and preserves presynaptic terminals in cultured hippocampal neurons exposed to etoposide. Collectively, these findings provide the first evidence for a local transcription-independent action of p53 in synapses, and suggest that such a local action of p53 may contribute to the dysfunction and degeneration of synapses that occurs in various neurodegenerative disorders.

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

“…Also, in cultured primary hippocampal neurons p53 becomes detectable in presynaptic terminals after etoposide exposure. This coincides with synaptic degeneration and again can be prevented by pifithrin-a pretreatment (Gilman et al, 2003;Culmsee and Mattson, 2005). Synaptic degeneration is thought to be a critical initial event for acute and chronic neurodegenerative diseases including stroke, Alzheimer's, Parkinson's and Huntington's disease.…”

Rescue of p53 Blockage by the A2AAdenosine Receptor via a Novel Interacting Protein, Translin-Associated Protein X

“…The roles of p53 in tumor formation and apoptosis therefore have been extensively investigated. In the central nervous system, p53 has been implicated in neuronal apoptosis caused by various stresses and disorders (Herzog et al, 1998;Gilman et al, 2003;Jordan et al, 2003;Bae et al, 2005). Moreover, in a widely used neuronal model (PC-12 cells), p53 and its downstream effector (p21) were shown to play critical roles in NGF-induced neuronal differentiation by causing cell cycle arrest (Lin et al, 1992;Eizenberg et al, 1996;Levine, 1997;Erhardt and Pittman, 1998).…”

Stress-Induced p53 Runs a Direct Mitochondrial Death Program: Its Role in Physiologic and Pathophysiologic Stress Responses In Vivo

“…Twenty-four hours later, neuronal synaptosomes (fractions that are highly enriched in synaptic buttons which contain mitochondria and synaptic vesicles; devoid of cell nuclei) as well as cell nuclei were isolated from tissue homogenates of the cortex. 17 Of note, total p53 and phosphoSer15-p53 protein levels were induced in neuronal nuclei as well as in synaptic terminals, but the relative etoposide-mediated p53 increase was higher in synaptosomes (210%) compared to nuclei (35%), suggesting that p53 may be locally produced or transported into synaptic terminals following an apoptotic insult in vivo. This synaptic p53 protein facilitates the collapse of mitochondrial membrane potential/dysfunction and the production of ROS upon oxidative and excitotoxic insults, since neuronal synaptosomes made from p53 -/-mice showed a significantly lower degree of these changes.…”

“…Conversely-and as already seen in renal tubular cells-pretreating synaptosomes with pifithrin-α preserved their mitochondrial membrane potential and partially blocked ROS production upon genotoxic, oxidative or excitotoxic insults. 17 Likewise, in cultured primary hippocampal neurons immunoreactive p53 is present in presynaptic terminals only after exposure to etoposide (but not in mock-treated controls), and p53's synaptic appearance coincides with synaptic degeneration. This again can be prevented by pretreating with pifithrin-α.…”

“…This again can be prevented by pretreating with pifithrin-α. 17 Synaptic dysfunction and degeneration are believed to be a critical initial event for many acute and chronic neurodegenerative diseases including stroke, Alzheimer's disease, Parkinson's disease and Huntington's disease. Together, the data support a transcription-independent action of synaptic p53 in neurons that directly controls mitochondrial dysfunction which then triggers synaptic degeneration and neuronal apoptosis.…”