PTEN deletion enhances survival, neurite outgrowth and function of dopamine neuron grafts to MitoPark mice

Abstract

Clinical trials in Parkinson’s disease have shown that transplants of embryonic mesencephalic dopamine neurons form new functional connections within the host striatum, but the therapeutic benefits have been highly variable. One obstacle has been poor survival and integration of grafted dopamine neurons. Activation of Akt, a serine/threonine kinase that promotes cell survival and growth, increases the ability of neurons to survive after injury and to regenerate lost neuronal connections. Because the lipid phosphatase, phosphatase and tensin homolog (PTEN) inhibits Akt, we generated a mouse with conditional knock-out of PTEN in dopamine neurons, leading to constitutive expression of Akt in these neurons. Ventral mesencephalic tissue from dopamine phosphatase and tensin homologue knock-out or control animals was then transplanted bilaterally into the dopamine depleted striata of MitoPark mice that express a parkinsonian phenotype because of severe respiratory chain dysfunction in dopamine neurons. After transplantation into MitoPark mice, PTEN-deficient dopamine neurons were less susceptible to cell death, and exhibited a more extensive pattern of fibre outgrowth compared to control grafts. Voltammetric measurements demonstrated that dopamine release and reuptake were significantly increased in the striata of animals receiving dopamine PTEN knock-out transplants. These animals also displayed enhanced spontaneous and drug-induced locomotor activity, relative to control transplanted MitoPark mice. Our results suggest that disinhibition of the Akt-signalling pathway may provide a valuable strategy to enhance survival, function and integration of grafted dopamine neurons within the host striatum and, more generally, to improve survival and integration of different forms of neural grafts.

MiR-92a regulates viability and angiogenesis of endothelial cells under oxidative stress

“…The PTEN/Akt pathway was reported to play a key role in cell survival under oxidative or nitrosative stress [27], with oxidative stress-mediated cell apoptosis correlating with increased PTEN expression and inhibition of AKT signaling [28]. PTEN gene deletion was reported to enhance cell survival by activation of the Akt pathway [29]. PTEN is the target of certain cellular miRNAs, including miR-19a/b [30], miR-29a [31], miR-214 [32], miR-205 [33] and miR-494 [34], which can directly suppress the expression of PTEN in a post-transcriptional manner.…”

Use of Retinal Explants to Examine the Effect of Granulocyte-Macrophage Colony-Stimulating Factor on Neurite Growth

“…Consistently, deletion of SOCS3 or PTEN in adult RGCs has been shown to promote axon regeneration and cell survival after optic nerve crush (Park et al, 2008;Smith et al, 2009). Similar effects have been observed in other CNS neurons (Liu et al, 2010;Zhang et al, 2012;Du et al, 2015). Moreover, codeletion of PTEN and SOCS3 in adult RGCs resulted in a striking synergistic effect on optic nerve regeneration; notably, some fibers reached brain regions and formed active synapses (Sun et al, 2011;Li et al, 2014).…”

The Protein Complex of Neurodegeneration-related Phosphoinositide Phosphatase Sac3 and ArPIKfyve Binds the Lewy Body-associated Synphilin-1, Preventing Its Aggregation

“…PARK6 and PARK20, are linked with the 3-and 5-phosphoinositide phosphatase activities of PTEN and SNJ1, respectively, both of which also harbor the signature C(X) 5 R(S/T) motif (55, 56). Reported alterations in mouse models with Pten-deficient dopaminergic neurons also corroborate the role of phosphoinositides (57). Furthermore, the central region of Sph1, which encompasses ankyrin repeats and the coiled-coil domain, is required for the formation of both multiple small aggregates in basal conditions and a single aggresome upon proteasome inhibition (39).…”