Pre-α-pro-GDNF and Pre-β-pro-GDNF Isoforms Are Neuroprotective in the 6-hydroxydopamine Rat Model of Parkinson's Disease

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Penttinen , A-M , Parkkinen , I , Voutilainen , M H , Koskela , M , Bäck , S , Their , A , Richie , C T , Domanskyi , A , Harvey , B K , Tuominen , R K , Nevalaita , L , Saarma , M & Airavaara , M 2018 , ' 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 , vol. 9 , 457 . https://doi.org/10.3389/fneur.2018.00457

Title: Pre-α-pro-GDNF and Pre-β-pro-GDNF Isoforms Are Neuroprotective in the 6-hydroxydopamine Rat Model of Parkinson's Disease
Author: Penttinen, Anna-Maija; Parkkinen, Ilmari; Voutilainen, Merja H.; Koskela, Maryna; Bäck, Susanne; Their, Anna; Richie, Christopher T.; Domanskyi, Andrii; Harvey, Brandon K.; Tuominen, Raimo K.; Nevalaita, Liina; Saarma, Mart; Airavaara, Mikko
Contributor organization: Institute of Biotechnology
Helsinki Institute of Life Science HiLIFE
Faculty of Pharmacy
Division of Pharmacology and Pharmacotherapy
Regenerative pharmacology group
Drug Research Program
Mart Saarma / Principal Investigator
Regenerative Neuroscience
Date: 2018-06-20
Language: eng
Number of pages: 14
Belongs to series: Frontiers in neurology
ISSN: 1664-2295
DOI: https://doi.org/10.3389/fneur.2018.00457
URI: http://hdl.handle.net/10138/264661
Abstract: Glial cell line-derived neurotrophic factor (GDNF) is one of the most studied neurotrophic factors. GDNF has two splice isoforms, full-length pre-alpha-pro-GDNF (u-GDNF) and pre-beta-pro-GDNF (beta-GDNF), which has a 26 amino acid deletion in the pro-region. Thus far, studies have focused solely on the u-GDNF isoform, and nothing is known about the in vivo effects of the shorter beta-GDNF variant. Here we compare for the first time the effects of overexpressed cx-GDNF and beta-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 u-GDNF enhanced the use of contralateral paw. Four weeks later, the striatal tyrosine hydroxylase (TH)-immunoreactivity was decreased in both u-GDNF and 1-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, beta-GDNF, and the full-length alpha-isoform have comparable neuroprotective efficacy on dopamine neurons of the nigrostriatal circuitry.
Subject: neurotrophic factors
neurodegeneration
GDNF
splice variant
alternative splicing
tyrosine hydroxylase
dopamine
MIDBRAIN DOPAMINERGIC-NEURONS
CONVECTION-ENHANCED DELIVERY
INTRASTRIATAL 6-OHDA LESION
AGED FISCHER-344 RATS
NEUROTROPHIC FACTOR
IN-VIVO
TYROSINE-HYDROXYLASE
LENTIVIRAL VECTOR
NIGROSTRIATAL PATHWAY
GENE-TRANSFER
3112 Neurosciences
Peer reviewed: Yes
Rights: cc_by_nc
Usage restriction: openAccess
Self-archived version: publishedVersion


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