Abstract
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.
Highlights
Purified from a rat glioma cell line, glial cellderived neurotrophic factor (GDNF) was shown to promote differentiation and survival of rat midbrain dopamine neurons, increase outgrowth of neurites and dopamine uptake in vitro [1]
Green fluorescent protein (GFP) expression in the SN reticulata was not in tyrosine hydroxylase (TH)-immunoreactive fibers or TH-immunoreactive cells of the substantia nigra pars compacta (SNpc) (Figure 2D). This staining pattern suggests that striatal delivery of scAAV1 does not transduce nigrostriatal dopaminergic neurons, but nigral gene expression is due to transduction of striatal medium spiny projection neurons
We found that overexpression with associated virus (AAV) under the CMV promoter in vivo both α-Glial cell line-derived neurotrophic factor (GDNF) and β-GDNF were found to be co-localized with the secretogranin II (scgII)-signal (Figure 2E)
Summary
Purified from a rat glioma cell line, glial cellderived neurotrophic factor (GDNF) was shown to promote differentiation and survival of rat midbrain dopamine neurons, increase outgrowth of neurites and dopamine uptake in vitro [1]. The pro-region has been suggested to play a role in the folding and secretion of GDNF [18] In vitro, both isoforms are secreted from the cells upon overexpression but in drastically different manner. The isoforms have different localization patterns inside the cells: α-GDNF is mainly localized in the Golgi complex, whereas β-GDNF is localized in secretogranin II (scgII)- and Rab3A-positive vesicles of the regulated secretory pathway [17]. Despite these differences in localization and secretion, the two major splice isoforms, α-GDNF and β-GDNF, are expressed in the same tissues, but in varying proportions [14,15,16]. Β-GDNF mRNA expression is present at relatively high levels during brain development when neuronal contacts are formed [15]
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