Tetanus toxin HC fragment reduces neuronal MPP+ toxicity

The non-toxic carboxi-terminal domain of the heavy chain of tetanus toxin (H-C) elicits neuroprotection of cerebellar granule neurons against apoptotic death induced by potassium deprivation. In this study we sought to determine whether H-C also prevents the apoptosis induced by the mitochondrial poison 1-methyl-4-phenylpyridinium (MPP+), which induces a form of Parkinsonism. Pre-treatment of cultures with H-C prevented MPP+-induced cell death, as well as impaired the MPP+-triggered apoptotic cascade. Cytochrome c release from the mitochondria, procaspase-3 activation and chromatin condensation, were significantly reduced in H-C-pretreated neurons. Moreover, H-C induced Ser(112) and Ser(136) BAD phosphorylation, which correlated with the detachment of BAD from BCl-X-L and its association to 14-3-3. In turn, Bcl-X-L remained bound to Bax, impairing its translocation to mitochondria of stressed neurons. The use of Wortmannin or PD98059 demonstrated the involvement of the PI3K/Akt as well as the ERK1/2 transduction pathways in the H-C fragment effect. Interestingly, the H-C fragment also induces an increase in the DNA binding activity of NF-kappa B, a well-established transcription factor involved in the prevention of neuronal death. Taken together, our results strongly suggest that the recombinant H-C fragment of tetanus toxin can act as a neuroprotector in a model of MPP+-triggered apoptosis. (C) 2009 Elsevier Inc. All rights reserved.