Role of pleiotrophin-protein tyrosine phosphatase receptor type Z signaling in myelination

Amyothrophic lateral sclerosis (ALS) is a disorder characterized by the progressive degeneration of motoneurons and subsequent weakness of the skeletal muscles. Respiratory insufficiency is the most common cause of death for these patients, and it occurs approximately within three years. Riluzole is the only drug that has shown a survival benefit, although it is limited to 6 months and offers no improvement in clinical symptoms (Miller et al., 2007). Bone marrow mononuclear cells have been proposed as a treatment for ALS (Deda et al., 2009). They can provide a neurotrophic effect and modulate the immune host environment. The benefits of bone marrow cells infusion into the spinal cord parenchyma of a SOD1-mutant mice, a model of motoneuron degeneration, has been tested by our group. After laminectomy, the cells were injected at the L5–S1 level, into the anterior horn of the spinal cord through the posterior funiculus. The mice experienced functional improvement as well as an increase in the number of motoneurons in the anterior horn of the spinal cord when compared with sham operated mice. However, no neural differentiation of the transplanted cells was observed (Pastor et al., 2012). These data generated in animal models support the evidence that the major mechanism of action of the bone marrow stem cells is based on trophic support by the production of molecules. These trophic factors are important in ALS and other diseases characterized by degeneration of spinal motoneurons (Suzuki and Sevendsen, 2008). In the case of the familial ALS mouse model SOD1 G93A, the main neurotrophic mediator is the glial derived neurotrophic factor (GDNF). It is able to prevent motoneuron degeneration although it does not promote muscle reinnervation or recovery of muscle function (Suzuki et al., 2007). Further analysis of the mice experimental spinal cords showed that the grafted cells formed cellular nests surrounding the motoneurons and that they expressed GDNF at the mRNA and protein level. This graft-derived GDNF acted as a neurotrophic signal in the microenvironment of spinal motoneurons, increasing neuronal survival, and improving the functional performance of the mice after the transplant (Pastor et al., 2012), in contrast to Suzuki et al. observations.