Parkinson Disease-associated DJ-1 Is Required for the Expression of the Glial Cell Line-derived Neurotrophic Factor Receptor RET in Human Neuroblastoma Cells

Object Investigation of fetal dopaminergic tissue transplantation is being conducted in animal models and clinical trials as a potential treatment for advanced Parkinson disease (PD). Because the availability of fetal tissue is limited, however, the duration of its storage prior to transplantation is a key practical issue. Longer storage times may enable fetal tissue obtained over several days to be pooled together for transplantation in a recipient. Glial cell line–derived neurotrophic factor (GDNF) has been shown to improve survival of stored human dopaminergic tissue prior to transplantation. The objective of this study was to evaluate GDNF-supplemented hibernation of fetal dopaminergic tissue for extended periods of 6 to 15 days. Methods A total of 27 rat ventral mesencephalons (VMs) were obtained in gestation Day 14 rat fetuses, and three were cultured immediately (fresh-culture control group). The remaining 24 VMs were divided sagittally along the mid-line to form 48 equal pieces of hemimesencephalons. Twenty-four pieces were stored with GDNF-supplemented hibernation medium for 6, 9, 12, or 15 days, and the 24 “partner” hemimesencephalons were stored in control hibernation medium for the same periods of time. Tissue was cultured for 48 hours and processed for tyrosine hydroxylase (TH) immunoreactivity and cresyl violet. Cell counts for all cultures and percentage of TH-immunoreactive cells were obtained. The percentage of TH-positive cells for the fresh control group was 6.3 ± 0.5%; that measured in cultures derived from tissue hibernated in GDNF-supplemented medium was significantly increased at 6 and 9 days posthiber-nation compared with the fresh-culture control group and the partner groups stored in hibernation medium only. No significant increase in percentage of TH-immunoreactive cells was observed in the 12- and 15-day hibernation groups. Conclusions In summary the authors found that fetal dopaminergic tissue can safely be stored up to 9 days in GDNF-supplemented hibernation medium. Furthermore the percentage of TH-immunoreactive cells is significantly increased after 6 and 9 days of storage in this medium, improving the yield of TH-positive cells prior to transplantation. These observations may have important clinical implications for collecting fetal dopaminergic cells and improving their survival after transplantation.

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Glial cell line—derived neurotrophic factor—supplemented hibernation of fetal ventral mesencephalic neurons for transplantation in Parkinson disease: long-term storage

Journal of Neurosurgery ◽

10.3171/jns.2003.98.5.1078 ◽

2003 ◽

Vol 98 (5) ◽

pp. 1078-1083 ◽

Cited By ~ 19

Author(s):

Adam O. Hebb ◽

Kari Hebb ◽

Arun C. Ramachandran ◽

Ivar Mendez

Keyword(s):

Parkinson Disease ◽

Cell Line ◽

Glial Cell ◽

Neurotrophic Factor ◽

Storage Time ◽

Fetal Tissue ◽

Control Group ◽

Content Type ◽

Cell Counts ◽

Fine Print

Object. Transplantation of fetal dopaminergic tissue is being investigated in animal models and clinical trials for its potential as a treatment for advanced Parkinson disease. At the same time, the availability of fetal tissue is limited, making its storage time prior to transplantation a key practical issue. Although it results in a smaller percentage of surviving cells, a longer storage time enables fetal tissue obtained over several days to be pooled for transplantation in a recipient. Glial cell line—derived neurotrophic factor (GDNF) has been shown to improve survival of human dopaminergic tissue that has been stored prior to transplantation. The objective of this study was to evaluate the effects on fetal dopaminergic tissue of GDNF-supplemented hibernation for extended periods of 6 to 15 days. Methods. The ventral mesencephalon (VM) was harvested in a total of 27 14-day-old rat fetuses, and three VMs were cultured immediately (fresh control group). The remaining 24 VMs were divided sagittally along the midline to yield 48 equal pieces of hemimesencephalon. Twenty-four pieces were stored with GDNF-supplemented hibernation medium for 6, 9, 12, or 15 days, and the 24 “partner” hemimesencephalon pieces were stored in control hibernation medium for the same periods of time. Tissue was cultured for 48 hours and processed for tyrosine hydroxylase (TH) immunoreactivity and double-stained with cresyl violet. Cell counts for all cultures and the percentage of TH-immunoreactive cells were obtained. The percentage of TH-immunoreactive cells for the fresh control group was 6.3 ± 0.5%. The percentage of TH-immunoreactive cells in cultures derived from tissue stored in GDNF-supplemented medium was significantly increased at 6 and 9 days posthibernation compared with the fresh control group and the “partner” groups stored in hibernation medium only. No significant increase in the percentage of TH-immunoreactive cells was observed in the 12- and 15-day groups. Conclusions. In this study the authors have demonstrated that fetal dopaminergic tissue can be safely stored for up to 9 days in GDNF-supplemented hibernation medium. Furthermore, the percentage of TH-immunoreactive cells is significantly increased after 6 and 9 days of storage in this medium, improving the yield of TH-immunoreactive cells prior to transplantation. These observations have practical clinical implications for collecting fetal dopaminergic cells and improving their survival after transplantation.

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Ciliary neurotrophic factor regulates nicotinic acetylcholine receptors on human neuroblastoma cells

Neuropharmacology ◽

10.1016/0028-3908(95)00168-9 ◽

1996 ◽

Vol 35 (3) ◽

pp. 257-265 ◽

Cited By ~ 11

Author(s):

S.W. Halvorsen ◽

R. Malek ◽

X. Wang ◽

N. Jiang

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Neurotrophic Factor ◽

Acetylcholine Receptors ◽

Neuroblastoma Cells ◽

Ciliary Neurotrophic Factor ◽

Human Neuroblastoma Cells ◽

Human Neuroblastoma ◽

Nicotinic Acetylcholine

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Early transplantation of an encapsulated glial cell line—derived neurotrophic factor—producing cell demonstrating strong neuroprotective effects in a rat model of Parkinson disease

Journal of Neurosurgery ◽

10.3171/jns.2005.102.1.0080 ◽

2005 ◽

Vol 102 (1) ◽

pp. 80-89 ◽

Cited By ~ 51

Author(s):

Takao Yasuhara ◽

Tetsuro Shingo ◽

Kenichiro Muraoka ◽

Kazuki Kobayashi ◽

Akira Takeuchi ◽

...

Keyword(s):

Parkinson Disease ◽

Cell Line ◽

Glial Cell ◽

Rat Model ◽

Neurotrophic Factor ◽

Dopaminergic Neurons ◽

Neuroprotective Effects ◽

Content Type ◽

Glial Proliferation ◽

Fine Print

Object. Glial cell line—derived neurotrophic factor (GDNF) has been shown to confer neuroprotective effects on dopaminergic neurons. The authors investigated the effects of GDNF on 6-hydroxydopamine (6-OHDA)—treated dopaminergic neurons in vitro and in vivo. Methods. First, the authors examined how 1, 10, or 100 ng/ml of GDNF, administered to cells 24 hours before, simultaneously with, or 2 or 4 hours after 6-OHDA was added, affected dopaminergic neurons. In a primary culture of E14 murine ventral mesencephalic neurons, earlier treatment with the higher dosage of GDNF suppressed 6-OHDA—induced loss of dopaminergic neurons better than later treatment. Next, the authors examined whether continuous infusion of GDNF at earlier time points would demonstrate a greater neuroprotective effect in a rat model of Parkinson disease (PD). They established a human GDNF-secreting cell line, called BHK-GDNF, and encapsulated the cells into hollow fibers. The encapsulated cells were unilaterally implanted into the striatum of adult rats 1 week before; simultaneously with; or 1, 2, or 4 weeks after 6-OHDA was given to induce lesions of the same striatum. With the earlier transplantation of a BHK-GDNF capsule, there was a significant reduction in the number of amphetamine-induced rotations displayed by the animals. Rats that had received earlier implantation of BHK-GDNF capsules displayed more tyrosine hydroxylase—positive neurons in the substantia nigra pars compacta and a tendency for glial proliferation in the striatum. Conclusions. These neuroprotective effects may be related to glial proliferation and signaling via the GDNF receptor α1. The results of this study support a role for this grafting technique in the treatment of PD.

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