PTEN Learn

PTEN Learn

Recent advances in neuroscience have drawn considerable attention to SCI research and are leading to the availability of better treatment and rehabilitation options.

However. therapies that promote axonal growth and functional recovery following SCI are limited. This is primarily due to the poor innate regenerative capacity of the adult central nervous system neurons and due to the hostile injury environment comprising inflammation, myelin- associated inhibitors, glial scar components and compromised blood supply.

Attempts to treat SCI by targeting extrinsic mechanisms controlling axonal regeneration have yielded limited success in complete SCI. Directions including extracellular inhibitory molecule removal, neurotrophic factor delivery and permissive substrate grafting have all failed to elicit robust regeneration of injured axons and substantial functional recovery.

As a major intrinsic impediment to axonal growth, PTEN is expressed in neurons and regenerating axons. It plays a vital role in controlling the regeneration of corticospinal neurons via downregulating cytoplasmic mammalian target of rapamycin (mTOR) activity.

This mTOR pathway is intensely inhibited in axotomized adult neurons, restricting protein synthesis that sustains axonal growth.

PTEN is a highly conserved dual-specificity protein tyrosine phosphatase. The protein dephosphorylates the lipid second messengers phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] and phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] to produce phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and phosphatidylinositol 4-phosphate [PI(4)P], respectively.

Growth Factors

This unique activity makes PTEN a major homeostatic regulator and tumor suppressor protein, which function is absent or defective in a wide variety of tumors as a result of somatic alterations. The important role of the PI3K/AKT/mTOR signaling pathway in cell growth, regeneration and survival supports the rationale for the therapeutic targeting of PTEN.

Among the suggested PTEN inhibition-based therapeutic targets are nerve growth and regeneration after injury or damage, treatment of cardiac ischemia/reperfusion and associated disease, wound repair, and infertility.

Interestingly, the main paradigm of PTEN involvement in cancer is as a cancer suppressor, and it has been shown that PTEN inhibition may occur in brain metastases. PTEN is expressed preferentially in the neurons in adult brains, plays a critical role in controlling the regeneration of corticospinal neurons via downregulation of mammalian target of rapamycin (mTOR) activity. The mTOR activity is profoundly suppressed in axotomized adult neurons, limiting new protein synthesis required for sustained axon regeneration.

Several publications mention involvement of PTEN in suppression of nerve regeneration and others showed the positive effect of PTEN depletion on conditions related to axon damage or impairment. Effective inhibition of PTEN would be a candidate for increasing mTOR thereby promoting nerve regeneration.

There is a vast number of vehicles suggested as useful for delivering siRNA molecules including liposomes, protein particles, micelles, and lipid particles among others. Rungta et al., (Molecular Therapy- Nucleic Acids, 2013, 2, el 36) showed that siRNA in lipid nanoparticles (LNP) may efficiently silence neuronal genes expression