Enhanced Efficacy of the CDNF/MANF Family by Combined Intranigral Overexpression in the 6-OHDA Rat Model of Parkinson's Disease
| Autor: | Oscar Cordero-Llana, Benjamin C Houghton, Rafael J. Yáñez-Muñoz, James B. Uney, Maeve A. Caldwell, Liang-Fong Wong, Federica Rinaldi, Hannah Taylor |
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| Rok vydání: | 2015 |
| Předmět: |
Tyrosine 3-Monooxygenase
Recombinant Fusion Proteins Genetic Vectors Gene Expression Substantia nigra Pharmacology Neuroprotection Cell Line chemistry.chemical_compound Transduction Genetic Neurotrophic factors Gene Order Drug Discovery Genetics Glial cell line-derived neurotrophic factor Animals Humans Nerve Growth Factors Oxidopamine Molecular Biology Cerebral dopamine neurotrophic factor Neurons Behavior Animal biology Lentivirus Dopaminergic Parkinson Disease Immunohistochemistry Rats Substantia Nigra Disease Models Animal Nerve growth factor nervous system chemistry biology.protein Molecular Medicine Original Article |
| Zdroj: | Molecular Therapy. 23:244-254 |
| ISSN: | 1525-0016 |
| Popis: | Cerebral Dopamine Neurotrophic Factor (CDNF) and Mesencephalic Astrocyte-derived Neurotrophic factor (MANF) are members of a recently discovered family of neurotrophic factors (NTFs). Here, we used intranigral or intrastriatal lentiviral vector-mediated expression to evaluate their efficacy at protecting dopaminergic function in the 6-OHDA model of Parkinson's disease (PD). In contrast to the well-studied Glial-Derived Neurotrophic Factor (GDNF), no beneficial effects were demonstrated by striatal overexpression of either protein. Interestingly, nigral overexpression of CDNF decreased amphetamine-induced rotations and increased tyroxine hydroxylase (TH) striatal fiber density but had no effect on numbers of TH(+) cells in the SN. Nigral MANF overexpression had no effect on amphetamine-induced rotations or TH striatal fiber density but resulted in a significant preservation of TH(+) cells. Combined nigral overexpression of both factors led to a robust reduction in amphetamine-induced rotations, greater increase in striatal TH-fiber density and significant protection of TH(+) cells in the SN. We conclude that nigral CDNF and MANF delivery is more efficacious than striatal delivery. This is also the first study to demonstrate that combined NTF can have synergistic effects that result in enhanced neuroprotection, suggesting that multiple NTF delivery may be more efficacious for the treatment of PD than the single NTF approaches attempted so far.Molecular Therapy (2014); doi:10.1038/mt.2014.206. |
| Databáze: | OpenAIRE |
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