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Functional Neuroprotection and Efficient Regulation of GDNF Using Destabilizing Domains in a Rodent Model of Parkinson's Disease

Quintino, Luis LU ; Manfre, Giuseppe LU ; Elgstrand, Erika LU ; Namislo, Angrit LU ; Isaksson, Christina LU and Lundberg, Cecilia LU (2013) In Molecular Therapy 21(12). p.2169-2180
Abstract
Glial cell line derived neurotrophic factor (GDNF) has great potential to treat Parkinson's disease (PD). However, constitutive expression of GDNF can over time lead to side effects. Therefore, it would be useful to regulate GDNF expression. Recently, a new gene inducible system using destabilizing domains (DD) from E. coil dihydrofolate reductase (DHFR) has been developed and characterized. The advantage of this novel DD is that it is regulated by trimethoprim (TMP), a well-characterized drug that crosses the blood brain barrier and can therefore be used to regulate gene expression in the brain. We have adapted this system to regulate expression of GDNF. A C-terminal fusion of GDNF and a DD with an additional furin cleavage site was able... (More)
Glial cell line derived neurotrophic factor (GDNF) has great potential to treat Parkinson's disease (PD). However, constitutive expression of GDNF can over time lead to side effects. Therefore, it would be useful to regulate GDNF expression. Recently, a new gene inducible system using destabilizing domains (DD) from E. coil dihydrofolate reductase (DHFR) has been developed and characterized. The advantage of this novel DD is that it is regulated by trimethoprim (TMP), a well-characterized drug that crosses the blood brain barrier and can therefore be used to regulate gene expression in the brain. We have adapted this system to regulate expression of GDNF. A C-terminal fusion of GDNF and a DD with an additional furin cleavage site was able to be efficiently regulated in vitro, properly processed and was able to bind to canonical GDNF receptors, inducing a signaling cascade response in target cells. In vivo characterization of the protein showed that it could be efficiently induced by TMP and it was only functional when gene expression was turned on. Further characterization in a rodent model of PD showed that the regulated GDNF protected neurons, improved motor behavior of animals and was efficiently regulated in a pathological setting. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Therapy
volume
21
issue
12
pages
2169 - 2180
publisher
Nature Publishing Group
external identifiers
  • wos:000328014500005
  • scopus:84890118525
ISSN
1525-0024
DOI
10.1038/mt.2013.169
language
English
LU publication?
yes
id
15ece165-49f1-47db-bd7a-4fb69ab9d7a2 (old id 4273097)
date added to LUP
2014-02-10 12:24:24
date last changed
2019-04-02 01:21:14
@article{15ece165-49f1-47db-bd7a-4fb69ab9d7a2,
  abstract     = {Glial cell line derived neurotrophic factor (GDNF) has great potential to treat Parkinson's disease (PD). However, constitutive expression of GDNF can over time lead to side effects. Therefore, it would be useful to regulate GDNF expression. Recently, a new gene inducible system using destabilizing domains (DD) from E. coil dihydrofolate reductase (DHFR) has been developed and characterized. The advantage of this novel DD is that it is regulated by trimethoprim (TMP), a well-characterized drug that crosses the blood brain barrier and can therefore be used to regulate gene expression in the brain. We have adapted this system to regulate expression of GDNF. A C-terminal fusion of GDNF and a DD with an additional furin cleavage site was able to be efficiently regulated in vitro, properly processed and was able to bind to canonical GDNF receptors, inducing a signaling cascade response in target cells. In vivo characterization of the protein showed that it could be efficiently induced by TMP and it was only functional when gene expression was turned on. Further characterization in a rodent model of PD showed that the regulated GDNF protected neurons, improved motor behavior of animals and was efficiently regulated in a pathological setting.},
  author       = {Quintino, Luis and Manfre, Giuseppe and Elgstrand, Erika and Namislo, Angrit and Isaksson, Christina and Lundberg, Cecilia},
  issn         = {1525-0024},
  language     = {eng},
  number       = {12},
  pages        = {2169--2180},
  publisher    = {Nature Publishing Group},
  series       = {Molecular Therapy},
  title        = {Functional Neuroprotection and Efficient Regulation of GDNF Using Destabilizing Domains in a Rodent Model of Parkinson's Disease},
  url          = {http://dx.doi.org/10.1038/mt.2013.169},
  volume       = {21},
  year         = {2013},
}