Abstract
Phosphatase and tensin homolog (PTEN) regulates apoptosis and axonal growth in the developing and adult central nervous system (CNS). Here, we show that human PTEN C-terminal PDZ interactions play a critical role in neuronal apoptosis and axon regeneration after traumatic CNS injury and stroke, highlighted by the findings that antagonizing the PDZ-motif interactions of PTEN has therapeutic applicability for these indications. Interestingly, the death-inducing function of PTEN following ischemic insult depends on a PDZ-domain interaction with MAGI-2 and MAST205, PDZ proteins that are known to recruit PTEN to the plasma membrane and stabilize its interaction with PIP3. Treatments with a human peptide that prevents PTEN association with MAGI-2 or MAST205 increased neuronal survival in multiple stroke models, in vitro. A pro-survival effect was also observed in models of retinal ischemia, optic nerve transection, and after middle cerebral artery occlusion (MCAO) in adult rats. The human PTEN peptide also improved axonal regeneration in the crushed optic nerve. Furthermore, human PTEN peptide therapy promoted functional improvement after MCAO or retinal ischemia induced via ophthalmic artery ligation. These findings show that the human peptide-based targeting of C-terminal PTEN PDZ interactions has therapeutic potential for insults of the CNS, including trauma and stroke.
Highlights
Adult mammalian central nervous system (CNS) neurons have limited regenerative capacity and are highly susceptible to apoptosis following injury[1,2]
Axonal regeneration was maximal in treatment with TAT-Phosphatase and tensin homolog (PTEN) via gelfoam (Fig. 5a, b; ***p < 0.001). These results demonstrate that the TAT-PTEN and R9PTEN peptides are capable of enhancing retinal ganglion cells (RGCs) axon regeneration following injury to the optic nerve
Regarding the mechanism of action, our findings show that TAT-PTEN or R9Conjugated PTEN peptides reduced the co-precipitation of MAGI-2 and Mast[205], demonstrating that the PTEN peptide blocked PTEN binding to these scaffolding proteins
Summary
Adult mammalian central nervous system (CNS) neurons have limited regenerative capacity and are highly susceptible to apoptosis (programmed cell death) following injury[1,2]. Factors of the CNS microenvironment contribute to this effect[3,4], including the absence of Schwann cells[1], and the accumulation of growth-inhibiting compounds at the injury site[5,6]. Inhibition of these antagonistic factors greatly improves axonal regeneration[7], indicating that modification of the downstream signals resulting from environmental contact presents a Ischemic CNS injury, encompassing brain and retinal ischemia, presents a significant health concern worldwide. Ischemic injury to the CNS represents a critical unmet need for therapeutic intervention
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