Pre-α-pro-GDNF and Pre-β-pro-GDNF Isoforms Are Neuroprotective in the 6-hydroxydopamine Rat Model of Parkinson's Disease
Glial cell line-derived neurotrophic factor (GDNF) is one of the most studied neurotrophic factors. GDNF has two splice isoforms, full-length pre-α-pro-GDNF (α-GDNF) and pre-β-pro-GDNF (β-GDNF), which has a 26 amino acid deletion in the pro-region. Thus far, studies have focused solely on the α-GDNF...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-06-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fneur.2018.00457/full |
| _version_ | 1818470321765744640 |
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| author | Anna-Maija Penttinen Ilmari Parkkinen Merja H. Voutilainen Maryna Koskela Susanne Bäck Anna Their Christopher T. Richie Andrii Domanskyi Brandon K. Harvey Raimo K. Tuominen Liina Nevalaita Mart Saarma Mikko Airavaara |
| author_facet | Anna-Maija Penttinen Ilmari Parkkinen Merja H. Voutilainen Maryna Koskela Susanne Bäck Anna Their Christopher T. Richie Andrii Domanskyi Brandon K. Harvey Raimo K. Tuominen Liina Nevalaita Mart Saarma Mikko Airavaara |
| author_sort | Anna-Maija Penttinen |
| collection | DOAJ |
| description | Glial cell line-derived neurotrophic factor (GDNF) is one of the most studied neurotrophic factors. GDNF has two splice isoforms, full-length pre-α-pro-GDNF (α-GDNF) and pre-β-pro-GDNF (β-GDNF), which has a 26 amino acid deletion in the pro-region. Thus far, studies have focused solely on the α-GDNF isoform, and nothing is known about the in vivo effects of the shorter β-GDNF variant. Here we compare for the first time the effects of overexpressed α-GDNF and β-GDNF in non-lesioned rat striatum and the partial 6-hydroxydopamine lesion model of Parkinson's disease. GDNF isoforms were overexpressed with their native pre-pro-sequences in the striatum using an adeno-associated virus (AAV) vector, and the effects on motor performance and dopaminergic phenotype of the nigrostriatal pathway were assessed. In the non-lesioned striatum, both isoforms increased the density of dopamine transporter-positive fibers at 3 weeks after viral vector delivery. Although both isoforms increased the activity of the animals in cylinder assay, only α-GDNF enhanced the use of contralateral paw. Four weeks later, the striatal tyrosine hydroxylase (TH)-immunoreactivity was decreased in both α-GDNF and β-GDNF treated animals. In the neuroprotection assay, both GDNF splice isoforms increased the number of TH-immunoreactive cells in the substantia nigra but did not promote behavioral recovery based on amphetamine-induced rotation or cylinder assays. Thus, the shorter GDNF isoform, β-GDNF, and the full-length α-isoform have comparable neuroprotective efficacy on dopamine neurons of the nigrostriatal circuitry. |
| first_indexed | 2024-04-13T21:35:50Z |
| format | Article |
| id | doaj.art-0e3d168a5c6044e79f9fcb0e3793f8c3 |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-04-13T21:35:50Z |
| publishDate | 2018-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-0e3d168a5c6044e79f9fcb0e3793f8c32022-12-22T02:28:57ZengFrontiers Media S.A.Frontiers in Neurology1664-22952018-06-01910.3389/fneur.2018.00457371449Pre-α-pro-GDNF and Pre-β-pro-GDNF Isoforms Are Neuroprotective in the 6-hydroxydopamine Rat Model of Parkinson's DiseaseAnna-Maija Penttinen0Ilmari Parkkinen1Merja H. Voutilainen2Maryna Koskela3Susanne Bäck4Anna Their5Christopher T. Richie6Andrii Domanskyi7Brandon K. Harvey8Raimo K. Tuominen9Liina Nevalaita10Mart Saarma11Mikko Airavaara12HiLIFE Unit, Institute of Biotechnology, University of Helsinki, Helsinki, FinlandHiLIFE Unit, Institute of Biotechnology, University of Helsinki, Helsinki, FinlandHiLIFE Unit, Institute of Biotechnology, University of Helsinki, Helsinki, FinlandHiLIFE Unit, Institute of Biotechnology, University of Helsinki, Helsinki, FinlandDivision of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, FinlandHiLIFE Unit, Institute of Biotechnology, University of Helsinki, Helsinki, FinlandNational Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, United StatesHiLIFE Unit, Institute of Biotechnology, University of Helsinki, Helsinki, FinlandNational Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, United StatesDivision of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, FinlandHiLIFE Unit, Institute of Biotechnology, University of Helsinki, Helsinki, FinlandHiLIFE Unit, Institute of Biotechnology, University of Helsinki, Helsinki, FinlandHiLIFE Unit, Institute of Biotechnology, University of Helsinki, Helsinki, FinlandGlial cell line-derived neurotrophic factor (GDNF) is one of the most studied neurotrophic factors. GDNF has two splice isoforms, full-length pre-α-pro-GDNF (α-GDNF) and pre-β-pro-GDNF (β-GDNF), which has a 26 amino acid deletion in the pro-region. Thus far, studies have focused solely on the α-GDNF isoform, and nothing is known about the in vivo effects of the shorter β-GDNF variant. Here we compare for the first time the effects of overexpressed α-GDNF and β-GDNF in non-lesioned rat striatum and the partial 6-hydroxydopamine lesion model of Parkinson's disease. GDNF isoforms were overexpressed with their native pre-pro-sequences in the striatum using an adeno-associated virus (AAV) vector, and the effects on motor performance and dopaminergic phenotype of the nigrostriatal pathway were assessed. In the non-lesioned striatum, both isoforms increased the density of dopamine transporter-positive fibers at 3 weeks after viral vector delivery. Although both isoforms increased the activity of the animals in cylinder assay, only α-GDNF enhanced the use of contralateral paw. Four weeks later, the striatal tyrosine hydroxylase (TH)-immunoreactivity was decreased in both α-GDNF and β-GDNF treated animals. In the neuroprotection assay, both GDNF splice isoforms increased the number of TH-immunoreactive cells in the substantia nigra but did not promote behavioral recovery based on amphetamine-induced rotation or cylinder assays. Thus, the shorter GDNF isoform, β-GDNF, and the full-length α-isoform have comparable neuroprotective efficacy on dopamine neurons of the nigrostriatal circuitry.https://www.frontiersin.org/article/10.3389/fneur.2018.00457/fullneurotrophic factorsneurodegenerationGDNFsplice variantalternative splicingtyrosine hydroxylase |
| spellingShingle | Anna-Maija Penttinen Ilmari Parkkinen Merja H. Voutilainen Maryna Koskela Susanne Bäck Anna Their Christopher T. Richie Andrii Domanskyi Brandon K. Harvey Raimo K. Tuominen Liina Nevalaita Mart Saarma Mikko Airavaara Pre-α-pro-GDNF and Pre-β-pro-GDNF Isoforms Are Neuroprotective in the 6-hydroxydopamine Rat Model of Parkinson's Disease Frontiers in Neurology neurotrophic factors neurodegeneration GDNF splice variant alternative splicing tyrosine hydroxylase |
| title | Pre-α-pro-GDNF and Pre-β-pro-GDNF Isoforms Are Neuroprotective in the 6-hydroxydopamine Rat Model of Parkinson's Disease |
| title_full | Pre-α-pro-GDNF and Pre-β-pro-GDNF Isoforms Are Neuroprotective in the 6-hydroxydopamine Rat Model of Parkinson's Disease |
| title_fullStr | Pre-α-pro-GDNF and Pre-β-pro-GDNF Isoforms Are Neuroprotective in the 6-hydroxydopamine Rat Model of Parkinson's Disease |
| title_full_unstemmed | Pre-α-pro-GDNF and Pre-β-pro-GDNF Isoforms Are Neuroprotective in the 6-hydroxydopamine Rat Model of Parkinson's Disease |
| title_short | Pre-α-pro-GDNF and Pre-β-pro-GDNF Isoforms Are Neuroprotective in the 6-hydroxydopamine Rat Model of Parkinson's Disease |
| title_sort | pre α pro gdnf and pre β pro gdnf isoforms are neuroprotective in the 6 hydroxydopamine rat model of parkinson s disease |
| topic | neurotrophic factors neurodegeneration GDNF splice variant alternative splicing tyrosine hydroxylase |
| url | https://www.frontiersin.org/article/10.3389/fneur.2018.00457/full |
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