Systems neuroscienceContinuous exposure to glial cell line-derived neurotrophic factor to mature dopaminergic transplants impairs the graft’s ability to improve spontaneous motor behavior in parkinsonian rats
Section snippets
Experimental design
In this study we analyzed the long-term effects of recombinant lentiviral vector (rLV) -mediated overexpression of GDNF on the fiber outgrowth and function of ventral mesencephalic (VM) grafts that were transplanted into the striatum several months prior to injection of viral vectors (Fig. 1). The rats received unilateral injections of 6-hydroxydopamine (6-OHDA) into the striatum in order to induce severe DA-denervating lesions, which are restricted to the striatum and leave the limbic and
Functional effects of GDNF-encoding lentiviral vectors on intrastriatal VM grafts
In this study, we analyzed the behavioral and morphological effects of GDNF, expressed long-term in the striatum using viral vector delivery, on mature intrastriatal VM grafts. Animals received severe DA-denervating lesions restricted to the striatum, and were included in the study when they performed ≤two adjusting steps in the stepping test which is indicative of a >80% DA denervation in the striatum. Animals then received intrastriatal transplants of fetal VM cells, which were allowed to
Discussion
The present study was designed to explore the effects of GDNF on the functional impact of fetal VM grafts in a rodent PD model. For this purpose, DA-depleted rats received intrastriatal transplants of fetal DA tissue that were spread over the whole striatum. Three months after transplantation, when graft-induced functional recovery was established, animals received intrastriatal injections of rLVs encoding for GDNF or GFP. Assessment of the motor behaviors at 3 months post–vector transduction
Conclusion
In conclusion, a number of critical issues can be raised for potential use of GDNF in conjunction with fetal nigral grafts. Since immature neuroblasts appear to be highly receptive to the actions of GDNF, this growth factor is likely to have a major impact on fetal nigral grafts at the time of, or shortly after grafting (i.e. within the first weeks after grafting). The major mode of action of GDNF during these first weeks after grafting is to increase cell survival and to induce fiber
Acknowledgments
This work was supported by grants from the Swedish Research Council (K2001-99-XG-13285-02B, K2002-33X-03874-30C, K2003-33P-14788-01A). We thank to Ulla Jarl, Anneli Josefson and Bengt Mattsson for excellent technical support.
References (71)
- et al.
Increased fiber outgrowth from xeno-transplanted human embryonic dopaminergic neurons with co-implants of polymer-encapsulated genetically modified cells releasing glial cell line-derived neurotrophic factor
Brain Res Bull
(2005) - et al.
Glial cell line-derived neurotrophic factor (GDNF) as a defensive molecule for neurodegenerative diseasea tribute to the studies of Antonia Vernadakis on neuronal-glial interactions
Int J Dev Neurosci
(2000) - et al.
Functional reinnervation from remaining DA terminals induced by GDNF lentivirus in a rat model of early Parkinson’s disease
Neurobiol Dis
(2006) - et al.
Survival and function of dissociated rat dopamine neurones grafted at different developmental stages or after being cultured in vitro
Dev Brain Res
(1988) - et al.
Loss of striatal DA innervation increases striatal trophic activity directed at DA neurons in culture
Exp Neurol
(1996) - et al.
Ontogeny and distribution of glial cell line-derived neurotrophic factor (GDNF) mRNA in rat
Brain Res Dev Brain Res
(1995) - et al.
Grafts of embryonic substantia nigra reinnervating the ventrolateral striatum ameliorate sensorimotor impairments and akinesia in rats with 6-OHDA lesions of the nigrostriatal pathway
Brain Res
(1981) - et al.
Aberrant sprouting and downregulation of tyrosine hydroxylase in lesioned nigrostriatal dopamine neurons induced by long-lasting overexpression of glial cell line derived neurotrophic factor in the striatum by lentiviral gene transfer
Exp Neurol
(2002) - et al.
Dopaminergic neural grafts after fifteen yearsresults and perspectives
Prog Neurobiol
(1994) - et al.
Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat
Exp Neurol
(1998)
Encapsulated GDNF-producing C2C12 cells for Parkinson’s diseasea pre-clinical study in chronic MPTP-treated baboons
Neurobiol Dis
Implantation of encapsulated catecholamine and GDNF-producing cells in rats with unilateral dopamine depletions and parkinsonian symptoms
Exp Neurol
Clinical observations after neural transplantation in Parkinson’s disease
Prog Brain Res
Effects of chronic intraputamenal infusion of glial cell line-derived neurotrophic factor (GDNF) in aged rhesus monkeys
Neurobiol Aging
The “staircase test”a measure of independent forelimb reaching and grasping abilities in rats
J Neurosci Methods
Restoration of complex sensorimotor behavior and skilled forelimb use by a modified nigral cell suspension transplantation approach in the rat Parkinson model
Neuroscience
Sequential administration of GDNF into the substantia nigra and striatum promotes dopamine neuron survival and axonal sprouting but not striatal reinnervation or functional recovery in the partial 6-OHDA lesion model
Exp Neurol
Implants of polymer-encapsulated genetically modified cells releasing glial cell line-derived neurotrophic factor improve survival, growth, and function of fetal dopaminergic grafts
Exp Neurol
Glial cell line-derived neurotrophic factor is expressed in the developing but not adult striatum and stimulates developing dopamine neurons in vivo
Exp Neurol
Quantitative recording of rotational behavior in rats after 6-hydroxydopamine lesions of the nigrostriatal system
Brain Res
Intranigral transplants of GABA-rich striatal tissue induce behavioral recovery in the rat Parkinson model and promote the effects obtained by intrastriatal dopaminergic transplants
Exp Neurol
Transplantation in the rat model of Parkinson’s diseaseectopic versus homotopic graft placement
Prog Brain Res
Cell transplantation in Parkinson’s diseasehow can we make it work?
Trends Neurosci
Sustained delivery of GDNFtowards a treatment for Parkinson’s disease
Brain Res Brain Res Rev
Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain
Nature
Intrastriatal injection of an adenoviral vector expressing glial-cell- line-derived neurotrophic factor prevents dopaminergic neuron degeneration and behavioral impairment in a rat model of Parkinson disease
Proc Natl Acad Sci U S A
Intracerebral grafting of neuronal cell suspensions. II. Survival and growth of nigral cell suspensions implanted in different brain sites
Acta Physiol Scand Suppl
Dopaminergic neurons protected from degeneration by GDNF gene therapy
Science
Transplantation in Parkinson’s diseasePET changes correlate with the amount of grafted tissue
Mov Disord
Effect of prior dopamine denervation on survival and fiber outgrowth from intrastriatal fetal mesencephalic grafts
Eur J Neurosci
Continuous low-level glial cell line-derived neurotrophic factor delivery using recombinant adeno-associated viral vectors provides neuroprotection and induces behavioral recovery in a primate model of Parkinson’s disease
J Neurosci
Neuroprotection in the rat Parkinson model by intrastriatal GDNF gene transfer using a lentiviral vector
Neuroreport
Dissociation between short-term increased graft survival and long-term functional improvements in Parkinsonian rats overexpressing glial cell line-derived neurotrophic factor
Eur J Neurosci
Overexpression of glial cell line-derived neurotrophic factor using a lentiviral vector induces time- and dose-dependent downregulation of tyrosine hydroxylase in the intact nigrostriatal dopamine system
J Neurosci
Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys
Brain
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Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson's Disease
2020, Cell Stem CellCitation Excerpt :First identified for its role in the survival and plasticity of embryonic midbrain DA neurons in culture (Lin et al., 1993), glial cell line-derived neurotrophic factor (GDNF) has been shown to increase the survival, plasticity, and metabolism of DA neurons in pre-clinical and clinical studies for PD (for reviews, see Björklund et al., 1997; Kirik et al., 2017; Thompson and Björklund, 2012). Recombinant GDNF protein has also been used to promote the survival of DA progenitors within fetal donor preparations prior to transplantation (Rosenblad et al., 1996), with studies in rodents and non-human primates demonstrating the benefits of prolonged delivery into the host tissue (via infusion) (Ahn et al., 2005; Johansson et al., 1995; Sinclair et al., 1996; Yurek, 1998) or injection of viral vectors) (Elsworth et al., 2008; Georgievska et al., 2004; Kauhausen et al., 2013; Redmond et al., 2009; Thompson et al., 2009; Wakeman et al., 2014; Winkler et al., 2006) for promoting survival, plasticity, and functionally appropriate integration of DA-rich fetal VM tissue grafts. Here, we have assessed the impact of long-term GDNF overexpression on hPSC-derived VM DA progenitor grafts.
GDNF-induced cerebellar toxicity: A brief review
2016, NeuroToxicologyCitation Excerpt :For example, GFRα-1 and GFRα-2 are progressively down-regulated in postnatal spinal motoneurons (Zhang and Huang, 2006), and exposure to toxins such as MPTP and rotenone effects a robust down-regulation of c-RET in neurons (Hirata and Kiuchi, 2007). Also, there are a number of studies reporting that chronic long-term over-expression of GDNF has adverse effects on both intact and Parkinsonian nigrostriatal neurons (Georgievska et al., 2004a,b; Winkler et al., 2006). A potential explanation for the latter findings is a direct negative feedback mechanism involving GDNF receptors.
Interrogating the aged striatum: Robust survival of grafted dopamine neurons in aging rats produces inferior behavioral recovery and evidence of impaired integration
2015, Neurobiology of DiseaseCitation Excerpt :The rationale for choosing this population of patients is valid in that these individuals represent the population most in need of alternative therapeutics; nevertheless, the impact of factors associated with the environment of the severely DA-depleted, aged striatum on the overall success of previous cell transplantation trials in PD remains incompletely understood. There have been painstaking efforts both in the clinic and the laboratory to characterize optimal donor cells used for cell transplantation therapy in PD, addressing issues including the source material for grafted cells, donor cell age, density of cell grafts, immune factors, and growth factors (e.g.: Steece-Collier et al., 1990; Annett et al., 1997; Freeman et al., 1995; Sladek et al., 1998; Collier et al., 1999; Freed et al., 2001; Winkler et al., 2006; Torres et al., 2007; Matarredona et al., 2003; Terpstra et al., 2007; Soderstrom et al., 2008; Bjorklund and Kordower, 2013). However, comparatively little has been done to determine the impact of the host environment on transplant success, with most of the attention given to defining the optimal transplant location (Strömberg et al., 1986; Goren et al., 2005; Breysse et al., 2007).
Intrastriatal GDNF gene transfer by inducible lentivirus vectors protects dopaminergic neurons in a rat model of parkinsonism
2014, Experimental NeurologyCitation Excerpt :Although lentivirus-mediated GDNF gene transfer into the brain of animal models of parkinsonism protects DA neurons from neurotoxin-induced cell death (Brizard et al., 2006; Georgievska et al., 2002a; Kordower et al., 2000), long-term overexpression of GDNF gene has been found to be associated with side effects including aberrant sprouting in the areas outside the striatum and down-regulation of tyrosine hydroxylase (TH) in the preserved DA terminals and intact striatum (Georgievska et al., 2002a, 2004b; Rosenblad et al., 2003). Furthermore, Winkler et al. reported that continuous exposure to GDNF impaired the ability of mature nigral transplants to improve spontaneous motor behavior in a rat model of parkinsonism (Winkler et al., 2006). It is therefore required to develop an inducible virus-mediated delivery system to regulate GDNF gene expression avoiding its related side effects.
Impact of dopamine to serotonin cell ratio in transplants on behavioral recovery and L-DOPA-induced dyskinesia
2011, Neurobiology of Disease