Phosphatidylinositol 3-kinase activity in murine motoneuron disease: The progressive motor neuropathy mouse

A murine model of motoneuron disease, the pmn/pmn mouse, shows a reduction in the retrograde transport of fluorescent probes applied directly onto the cut end of sciatic nerve. Brain-derived neurotrophic factor (BDNF), when c o-applied with fluorescent tracers, increases the number of retrograde labe lled motoneurons. We demonstrate here that spinal cord tissue from pmn/pmn mice had significantly reduced phosphatidylinositol 3-kinase activity and e xpression in the particulate fraction compared to controls. without changes in the activities or expression of the downstream kinases, protein kinase B/Akt or Erk1. Systemic administration of BDNF augmented phosphatidylinosit ol 3-kinase specific activity in spinal cord tissue from pmn/pmn and contro l mice, with a greater elevation in the particulate fractions of pmn/pmn mi ce than in controls. We examined the effect of inhibitors of phosphatidylin ositol 3-kinase and mitogen-activated protein kinase kinase on the retrogra de labelling of motoneurons. 24 h following the direct application of inhib itors and Fluorogold to the cut end of sciatic nerve in control and pmn/pmn mice (labelling index). The mitogen-activated protein kinase kinase inhibi tor PD 98059 had no effect on the labelling index in control or pmn/pmn mic e. In the absence of exogenous BDNF, phosphatidylinositol 3-kinase inhibito rs reduced the number of labelled motoneurons in control mice, without chan ging the labelling index in pmn/pmn. Co-application of phosphatidylinositol 3-kinase inhibitors with BDNF to the cut end of sciatic nerve blocked the action of BDNF on retrograde labelling in pmn/pmn mice. These results indicate that the retrograde labelling of motoneurons is medi ated by phosphatidylinositol 3-kinase-dependent and -independent pathways. In pmn/pmn mice, phosphatidylinositol 3-kinase activity in spinal neurons i s below the level required for optimal retrograde labelling of motoneurons and labelling can be augmented by the administration of growth factors stim ulating phosphatidylinositol 3-kinase activity. The data indicate that phos phatidylinositol 3-kinase activity is important in the uptake and/or retrog rade transport of substances by motoneurons and is altered in this model of motoneuron diseases. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.