Membrane-permeable Bcl-xL prevents MPTP-induced dopaminergic neuronal loss in the substantia nigra.
The anti-apoptotic Bcl-xL is a promising agent to prevent neurodegeneration in Parkinson's disease, which is characterized by a demise of dopaminergic neurons. We linked Bcl-xL to a peptide that allows its delivery across biological membranes and the blood-brain barrier. We tested the fusion protein in two models of Parkinson's Disease. Cell-permeable Bcl-xL protected neuroblastoma cells from the selective neurotoxin 1-methyl-4-phenylpyridinium. Furthermore, its systemic application in aged mice protected dopaminergic neurons following administration of MPTP as revealed by counting of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta. Hence, we present that a cell-permeable form of an anti-apoptotic protein can be delivered to CNS neurons through its systemic application, and we provide the proof that the delivery of this protein to the CNS neurons effectively prevents neuronal cell death in models of chronic neurodegenerative diseases.
Dietz
Gunnar P H
GP
Neurologische Universitätsklinik, Göttingen, Germany. gdietz@gwdg.de
Stockhausen
Kerstin V
KV
Dietz
Birgit
B
Falkenburger
Björn H
BH
Valbuena
Paola
P
Opazo
Felipe
F
Lingor
Paul
P
Meuer
Katrin
K
Weishaupt
Jochen H
JH
Schulz
Jörg B
JB
Bähr
Mathias
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology*; D010300:Parkinson Disease / Q000473:pathology; D011994:Recombinant Proteins / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology*; D051020:bcl-X Protein / Q000378:metabolism*
C494812:Bcl2l1 protein, mouse; D009498:Neurotoxins; D011994:Recombinant Proteins; D051020:bcl-X Protein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine