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Glial cell line-derived neurotrophic factor is crucial for long-term maintenance of the nigrostriatal system
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
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2010 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 171, no 4, 1357-1366 p.Article in journal (Refereed) Published
Abstract [en]

Glial cell line-derived neurotrophic factor (GDNF) is a potent factor for the ventral mesencephalic dopamine neurons. However, studies on the Gdnf gene deleted (Gdnf(-/-)) mouse have been limited to fetal tissue since these mice die prematurely. To evaluate long-term effects of Gdnf gene deletion, this study involves co-grafts of ventral mesencephalon (VM) and lateral ganglionic eminence (LGE) derived from different Gdnf genotypes. The VM/LGE co-grafts were evaluated at 3, 6, and 12 months for tyrosine hydroxylase (TH) -positive cell survival and nerve fiber formation in the LGE co-transplant, visualized by dopamine- and cyclic AMP-regulated phosphoprotein relative molecular mass 32,000 (DARPP-32) -immunoreactivity. Cell counts revealed no difference in TH-positive neurons between Gdnf genotypes at 3 months postgrafting. At 6 months, a significant reduction in cell number was observed in the Gdnf(-/-) grafts. In fact, in the majority of the Gdnf(-/-) VM/LGE transplant had degenerated. At 12 months, a reduction in cell number was seen in both Gdnf(-/-) and Gdnf(+/-) compared to wild type transplants. In the Gdnf(-/-) grafts, TH-negative inclusion-like structures were present in the cytoplasm of the TH-positive neurons at 3 months. These structures were also found in the Gdnf(+/-) transplants at 12 months, but not in Gdnf(+/+) controls at any time point. In Gdnf(+/+) grafts, TH-positive nerve fiber innervation of the striatal co-grafts was dense and patchy and overlapped with clusters of DARPP-32-positive neurons. This overlap did mismatch in the Gdnf(+/-) grafts, while the TH-positive innervation was sparse in the Gdnf(-/-) transplants and the DARPP-32-positive neurons were widespread distributed. In conclusion, GDNF is essential for long-term maintenance of both the VM TH-positive neurons and for the striatal tissue, and appears crucial for generation of a proper organization of the striatum.

Place, publisher, year, edition, pages
Elsevier, 2010. Vol. 171, no 4, 1357-1366 p.
Keyword [en]
GDNF, transplant, substantia nigra, striatum, DARPP-32, Gdnf knockout
National Category
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-41351DOI: 10.1016/j.neuroscience.2010.10.010ISI: 000285231000035PubMedID: 20933580OAI: oai:DiVA.org:umu-41351DiVA: diva2:405691
Available from: 2011-03-23 Created: 2011-03-23 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Dysfunction in the nigrostriatal system: effects of L-DOPA and GDNF
Open this publication in new window or tab >>Dysfunction in the nigrostriatal system: effects of L-DOPA and GDNF
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Parkinson’s disease is a common neurodegenerative disorder caused by nigrostriatal dopamine loss, with motor deficiencies as the primary outcome. To increase the striatal dopamine content, patients are treated with 3,4-dihydroxyphenyl-l-alanine (l-DOPA). Beneficial relief of the motor symptoms is achieved initially, although the efficacy is lost with time and severe side effects, referred to as l-DOPA-induced dyskinesia, manifest in the majority of patients. Biological mechanisms responsible for the dopaminergic degeneration and the upcoming of dyskinesia are still unclear, and thus knowledge regarding critical factors for maintenance of the nigrostriatal system as well as neurochemical changes upon chronic l-DOPA is urgent. The present work aims at studying the importance of glial cell line-derived neurotrophic factor (GDNF) for nigrostriatal preservation, and the involvement of the dopaminergic, serotonergic, and glutamatergic systems in l-DOPA-induced dyskinesia. Effects from different levels of GDNF expression were evaluated on fetal mouse nigrostriatal tissue in a grafting study. In GDNF gene-deleted grafts, degeneration of the entire nigrostriatal system was evident at 6 months. In grafts with partial GDNF expression, significant loss of dopamine neurons was observed at later time points, although deviant findings in the dopamine integrity such as reduced innervation capacity and presence of intracellular inclusions-like structures were already present at earlier stages. The results emphasize GDNF as a crucial factor for long-term maintenance of the nigrostriatal system. Furthermore, striatal neurochemical alterations upon chronic l-DOPA treatment were studied in hemiparkinsonian rats using in vivo voltametry. The findings demonstrated impaired dopamine as well as glutamate releases in dyskinetic subjects, with no effects from acute l-DOPA administration. Conversely, in l-DOPA naïve dopamine-lesioned animals, dopamine release was increased and glutamate release attenuated upon a l-DOPA challenge. Moreover, l-DOPA-derived dopamine release was demonstrated to originate from serotonergic nerve fibers in the dopamine-lesioned striatum, an event that contributes significantly to dopamine levels also in intact striatum, and thus, is not a consequence from dopamine depletion. Assessment of serotonergic nerve fibers in l-DOPA treated animals and in a grafting study concluded that nerve fiber density was not affected by chronic l-DOPA treatment, nevertheless, dysfunction of this system can be suspected in dyskinetic animals since dopamine release was impaired and regulation of glutamate release by serotonergic 5-HT1A receptor activation was achieved in normal but not in dyskinetic animals. Furthermore, the selective serotonin reuptake inhibitor, fluoxetine, attenuated l-DOPA-induced dyskientic behavior, an effect that was demonstrated to be mediated via 5-HT1A receptors. In conclusion, dysmodulation of multiple transmitter systems is evident in LID. 

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2013. 88 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1544
Keyword
Parkinson’s disease, L-DOPA, dyskinesia, GDNF, dopamine, glutamate, serotonin
National Category
Pharmaceutical Sciences Neurosciences
Research subject
Developmental Neurosciences
Identifiers
urn:nbn:se:umu:diva-64149 (URN)9789174595444 (ISBN)
Public defence
2013-02-08, BiA201, Biologihuset, Umeå universitet, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2013-01-18 Created: 2013-01-17 Last updated: 2013-01-18Bibliographically approved
2. GDNF and alpha-synuclein in nigrostriatal degeneration
Open this publication in new window or tab >>GDNF and alpha-synuclein in nigrostriatal degeneration
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Parkinson’s disease is a common neurological disorder with a complex etiology. The disease is characterized by a progressive loss of dopaminergic cells in the substantia nigra, which leads to motor function and sometimes cognitive function disabilities. One of the pathological hallmarks in Parkinson’s disease is the cytoplasmic inclusions called Lewy bodies found in the dopamine neurons. The aggregated protein α-synuclein is a main component of Lewy bodies. In view of severe symptoms and the upcoming of problematic side effects that are developed by the current most commonly used treatment in Parkinson’s disease, new treatment strategies need to be elucidated. One such strategy is replacing the lost dopamine neurons with new dopamine-rich tissue. To improve survival of the implanted neurons, neurotrophic factors have been used. Glial cell line-derived neurotrophic factor (GDNF), which was discovered in 1993, improves survival of ventral mesencephalic dopamine neurons and enhances dopamine nerve fiber formation according to several studies. Thus, GDNF can be used to improve dopamine-rich graft outgrowth into the host brain as well as inducing sprouting from endogenous remaining nerve fibers. This study was performed on Gdnf gene-deleted mice to investigate the role of GDNF on the nigrostriatal dopamine system. The transplantation technique was used to create a nigrostriatal microcircuit from ventral mesencephalon (VM) and the lateral ganglionic eminence (LGE) from different Gdnf gene-deleted mice. The tissue was grafted into the lateral ventricle of wildtype mice. The results revealed that reduced concentrations of GDNF, as a consequence from the Gdnf gene deletion, had effects on survival of dopamine neurons and the dopamine innervation of the nigrostriatal microcircuit. All transplants had survived at 3 months independently of Gdnf genotype, however, the grafts derived from Gdnf gene-deleted tissue had died at 6 months. Transplants with partial Gdnf gene deletion survived up to 12 months after transplantation. Moreover, the dopaminergic innervation of striatal co-grafts was impaired in Gdnf gene-deleted tissue. These results highlight the role of GDNF for long-term maintenance of the nigrostriatal dopamine system. To further investigate the role of GDNF expression on survival and organization of the nigrostriatal dopamine system, VM and LGE as single or combined to double co-grafts created from mismatches in Gdnf genotypes were transplanted into the lateral ventricle of wildtype mice. Survival of the single grafts was monitored over one year using a 9.4T MR scanner. The size of single LGE transplants was significantly reduced by the lack of GDNF already at 2 weeks postgrafting while the size of single VM was maintained over time, independently of GDNF expression. The double grafts were evaluated at 2 months, and the results revealed that lack of GDNF in LGE reduced the dopamine cell survival, while no loss of dopamine neurons was found in VM single grafts. The dopaminergic innervation of LGE was affected by absence of GDNF, which also caused a disorganization of the striatal portion of the co-grafts. Small, cytoplasmic inclusions were frequently found in the dopamine neurons in grafts lacking GDNF expression. These inclusions were not possible to classify as Lewy bodies by immunohistochemistry and the presence of phospho-α-synuclein and ubiquitin; however, mitochondrial dysfunction could not be excluded. To further study the death of the dopamine neurons by the deprivation of GDNF, the attention was turned to how Lewy bodies are developed. With respect to the high levels of α-synuclein that was found in the striatum, this area was selected as a target to inject the small molecule – FN075, which stimulates α-synuclein aggregation, to further investigate the role of α-synuclein in the formation of cytoplasmic inclusions. The results revealed that cytoplasmic inclusions, similar to those found in the grafts, was present at 1 month after the injection, while impairment in sensorimotor function was exhibited, the number of dopamine neurons was not changed at 6 months after the injection. Injecting the templator to the substantia nigra, however, significantly reduced the number of TH-positive neurons at 3 months after injection. In conclusion, these studies elucidate the role of GDNF for maintenance and survival of the nigrostriatal dopamine system and mechanisms of dopamine cell death using small molecules that template the α-synuclein aggregation.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2014. 61 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1665
Keyword
Parkinson's disease, GDNF, ventral mesencephalon, lateral ganglionic eminence, alpha-synuclein
National Category
Neurosciences
Research subject
Developmental Neurosciences
Identifiers
urn:nbn:se:umu:diva-91811 (URN)978-91-7601-098-3 (ISBN)
Public defence
2014-09-18, BiA201, IMB, Biologihuset, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2014-08-28 Created: 2014-08-18 Last updated: 2014-12-18Bibliographically approved

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