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Ciliary neurotrophic factor fused to a protein transduction domain retains full neuroprotective activity in the absence of cytokine‐like side effects
Author(s) -
Rezende Alexandre C.,
Peroni Daniele,
Vieira Andrè S.,
Rogerio Fabio,
Talaisys Rafael L.,
Costa Fabio T. M.,
Langone Francesco,
Skaper Stephen D.,
Negro Alessandro
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06091.x
Subject(s) - ciliary neurotrophic factor , motor neuron , neuroprotection , ciliary ganglion , biology , neurotrophic factors , cytokine , medicine , neuroscience , endocrinology , microbiology and biotechnology , spinal cord , immunology , receptor
Ciliary neurotrophic factor (CNTF) is a multifunctional cytokine that can regulate the survival and differentiation of many types of developing and adult neurons. CNTF prevents the degeneration of motor neurons after axotomy and in mouse mutant progressive motor neuronopathy, which has encouraged trials of CNTF for human motor neuron disease. Given systemically, however, CNTF causes severe side effects, including cachexia and a marked immune response, which has limited its clinical application. The present work describes a novel approach for administering recombinant human CNTF (rhCNTF) while conserving neurotrophic activity and avoiding deleterious side effects. rhCNTF was fused to a protein transduction domain derived from the human immunodeficiency virus‐1 TAT (transactivator) protein. The resulting fusion protein (TAT‐CNTF) crosses the plasma membrane within minutes and displays a nuclear localization. TAT‐CNTF was equipotent to rhCNTF in supporting the survival of cultured chicken embryo dorsal root ganglion neurons. Local or subcutaneous administration of TAT‐CNTF, like rhCNTF rescued motor neurons from death in neonatal rats subjected to sciatic nerve transection. In contrast to subcutaneous rhCNTF, which caused a 20–30% decrease in body weight in neonatal rats between postnatal days 2 and 7 together with a considerable fat mobilization in brown adipose tissue, TAT‐CNTF lacked such side effects. Together, these results indicate that rhCNTF fused with the protein transduction domain/TAT retains neurotrophic activity in the absence of CNTFs cytokine‐like side effects and may be a promising candidate for the treatment of motor neuron and other neurodegenerative diseases.