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: University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Institute of Biotechnology
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Institute of Biotechnology
University of Helsinki, Mart Saarma / Principal Investigator
University of Helsinki, Institute of Biotechnology
Date: 2018-06-20
Language: eng
Number of pages: 14
Belongs to series: Frontiers in neurology
ISSN: 1664-2295
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
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