Application of a blood-brain-barrier-penetrating form of GDNF in a mouse model for Parkinson's disease.
Glial-cell-line-derived neurotrophic factor (GDNF) promotes mesencephalic dopaminergic neuronal survival in several in vitro and in vivo models. As the demise of dopaminergic neurons is the cause for Parkinson's disease (PD) symptoms, GDNF is a promising agent for its treatment. However, this neurotrophin is unable to cross the blood-brain barrier, which has complicated its clinical use. Therefore, ways to deliver GDNF into the central nervous system in an effective manner are needed. The HIV-1-Tat-derived cell-penetrating peptide (CPP) provides a means to deliver fusion proteins into the brain. We generated a fusion protein between the 11 amino acid CPP of Tat and the rat GDNF mature protein to deliver GDNF across the blood-brain barrier. We showed previously that Tat-GDNF enhances the neuroprotective effect of GDNF in in vivo models for nerve trauma and ischemia. Here, we tested its effect in a subchronic scheme of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) application into the mouse as a model for PD to evaluate the effect of Tat-GDNF fusion protein in dopaminergic neuron survival. We showed that the fusion protein did indeed reach the dopaminergic neurons. However, the in vivo application of Tat-GDNF did not provide neuroprotection of dopaminergic neurons, as revealed by immunohistochemistry and counting of the number of tyrosine-hydroxylase-immunoreactive neurons in the substantia nigra pars compacta. Possibly, GDNF does protect nigro-striatal projections of those neurons that survive MPTP treatment but does not increase the number of surviving dopaminergic neurons. A concomitant treatment of Tat-GDNF with an anti-apoptotic Tat-fusion protein might be beneficial.
Dietz
Gunnar P H
GP
Neurologische Universitätsklinik, Waldweg 33, 37073 Göttingen, Germany. gdietz@gwdg.de
Valbuena
Paoloa C
PC
Dietz
Birgit
B
Meuer
Katrin
K
Müeller
Patrick
P
Weishaupt
Jachen H
JH
Bähr
Mathias
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology*; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D004347:Drug Interactions; D015696:Gene Products, tat / Q000627:therapeutic use; D018014:Gene Transfer Techniques; D015756:Genes, tat; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000627:therapeutic use*; D007150:Immunohistochemistry / Q000379:methods; D016086:Lentivirus; D051379:Mice; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology; D010455:Peptides / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015696:Gene Products, tat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D010455:Peptides; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase