Overexpression of human HSP27 protects sensory neurons from diabetes.

OBJECTIVES: To evaluate whether augmenting neuronal protective mechanisms might slow or arrest experimental diabetic peripheral neuropathy (DPN). DPN is one of the most common neurodegenerative disorders and is rising in prevalence. How it targets sensory neurons is uncertain; the disorder is irreversible and untreatable. We explored the intrinsic protective properties of overexpressed human HSP27 on experimental DPN. HSP27 is a small pro-survival heat shock protein that also increases axonal regeneration. METHODS: Experimental diabetes was superimposed on mice overexpressing a human HSP27 transgene and its impact was evaluated on epidermal innervation, behavioral tests of sensation and electrophysiological indices of DPN. RESULTS: Mice that overexpress human HSP27 in their sensory and motor neurons and that were made diabetic for 6 months by streptozotocin treatment were protected from a range of neuropathic abnormalities, including loss of footpad thermal sensation, mechanical allodynia, loss of epidermal innervation, and slowing of sensory conduction velocity. The protection was selective for sensory neurons in comparison to motor neurons and at 6 months provided better protection in female than male mice. Markers of RAGE-NFκB activation were attenuated by the transgene. CONCLUSIONS: The findings support the idea that diabetic polyneuropathy involves a unique, sensory-centric neurodegenerative process which can be reduced by overexpressing a single gene, an important starting point for new disease-modifying therapeutic approaches.

Synergistic effects of osteonectin and brain-derived neurotrophic factor on axotomized retinal ganglion cells neurite outgrowth via the mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 pathways.

Our previous study identified osteonectin (ON) in a screen of factors made by Schwann cells (SCs) which promoted peripheral and central neurons survival and neuritogenesis, however, the mechanisms of ON promoting effects are largely unknown. In the present study, we investigated the effects of ON-deficient SC-conditioned medium (SCCM) and molecular mechanisms of ON, in regulating retinal ganglion cells (RGCs) survival and neurite outgrowth. Neonatal rat RGCs and SCs were purified by immunopanning technique. RGC survival and neuritogenesis reduced significantly when treated with either ON-null mice SCCM or ON-immunodepleted (IP) SCCM (P<0.05). In contrast to wild type SCCM, in the presence of a tyrosine kinase receptor (Trk) inhibitor (K252a), ON-null mice SCCM-induced neuritogenesis were further reduced by 24%. The Trk-mediated signaling pathways became more sensitive to K252a inhibition in the absence of ON. We also showed the synergistic effects of ON and brain-derived neurotrophic factor (BDNF) in promoting RGCs growth and the involvement of ON in two major neurotrophin-mediated signaling pathways, PI-3K-Akt and MAPK-Erk1/2. ON alone activated Akt phosphorylation and increased survival. Blockage of TrkB signalling pathway by TrkB-Fc chimera (BDNF scavenger) or K252a in ON-treated cultures reduced Akt-P level significantly. This suggests that ON induces BDNF synthesis and secretion from RGCs. The enhancement of neuritogenesis and Erk1/2 phosphorylation by ON in BDNF-treated cultures further demonstrate the signaling pathways responsible for the synergistic effect of ON on BDNF-induced neurite outgrowth. To the best of our knowledge, this is the first report showing the synergistic effects of ON on classical neurotrophins which participate in the same signalling pathways in regulating RGC neurite outgrowth.