title: Enhanced efficacy of the CDNF/MANF family by combined intranigral overexpression in the 6-OHDA rat model of Parkinson's disease.
abstract: 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.
authors.affiliation: School of Clinical Sciences, Medical Sciences Building, University Walk, Bristol, UK.
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Cordero-Llana
authors.affiliation: School of Clinical Sciences, Medical Sciences Building, University Walk, Bristol, UK.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Houghton
authors.affiliation: School of Clinical Sciences, Medical Sciences Building, University Walk, Bristol, UK.
authors.forename: Federica
authors.initials: F
authors.lastname: Rinaldi
authors.affiliation: School of Clinical Sciences, Medical Sciences Building, University Walk, Bristol, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Taylor
authors.affiliation: School of Biological Sciences, Royal Holloway, University of London, Egham, UK.
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Yáñez-Muñoz
authors.affiliation: 1] School of Clinical Sciences, Medical Sciences Building, University Walk, Bristol, UK [2] Regenerative Medicine Laboratory, Medical Sciences Building, University Walk, Bristol, UK.
authors.forename: James B
authors.initials: JB
authors.lastname: Uney
authors.affiliation: 1] School of Clinical Sciences, Medical Sciences Building, University Walk, Bristol, UK [2] Regenerative Medicine Laboratory, Medical Sciences Building, University Walk, Bristol, UK.
authors.forename: Liang-Fong
authors.initials: LF
authors.lastname: Wong
authors.affiliation: 1] School of Clinical Sciences, Medical Sciences Building, University Walk, Bristol, UK [2] Regenerative Medicine Laboratory, Medical Sciences Building, University Walk, Bristol, UK.
authors.forename: Maeve A
authors.initials: MA
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002460:Cell Line; D004195:Disease Models, Animal; D015870:Gene Expression; D023061:Gene Order; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016627:Oxidopamine / Q000009:adverse effects; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D051381:Rats; D011993:Recombinant Fusion Proteins; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D014161:Transduction, Genetic; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C577430:CDNF protein, rat; C546826:MANF protein, rat; D009414:Nerve Growth Factors; D011993:Recombinant Fusion Proteins; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase