Nuclear trafficking of Pten after brain injury leads to neuron survival not death
Goh, CP and Putz, U and Howitt, J and Low, LH and Gunnersen, J and Bye, N and Morganti-Kossman, C and Tan, SS, Nuclear trafficking of Pten after brain injury leads to neuron survival not death, Experimental neurology, 252 pp. 37-46. ISSN 0014-4886 (2014) [Refereed Article]
There is controversy whether accumulation of the tumor suppressor PTEN protein in the cell nucleus under stress
conditions such as trauma and stroke causes cell death. A number of in vitro studies have reported enhanced
apoptosis in neurons possessing nuclear PTEN, with the interpretation that its nuclear phosphatase activity
leads to reduction of the survival protein phospho-Akt. However, there have been no in vivo studies to show
that nuclear PTEN in neurons under stress is detrimental. Using a mouse model of injury, we demonstrate here
that brain trauma altered the nucleo-cytoplasmic distribution of Pten, resulting in increased nuclear Pten but
only in surviving neurons near the lesion. This event was driven by Ndfip1, an adaptor and activator of protein
ubiquitination by Nedd4 E3 ligases. Neurons next to the lesion with nuclear PTEN were invariably negative for
TUNEL, a marker for cell death. These neurons also showed increased Ndfip1 which we previously showed to
be associated with neuron survival. Biochemical assays revealed that overall levels of Pten in the affected cortex
were unchanged after trauma, suggesting that Pten abundance globally had not increased but rather Pten
subcellular location in affected neurons had changed. Following experimental injury, the number of neurons
with nuclear Pten was reduced in heterozygous mice (Ndfip1+/−) although lesion volumes were increased.
We conclude that nuclear trafficking of Pten following injury leads to neuron survival not death.