Increased Physiological GDNF Levels Have No Effect on Dopamine Neuron Protection and Restoration in a Proteasome Inhibition Mouse Model of Parkinson’s Disease
Olfat, Soophie ; Mätlik, Kärt ; Kopra, Jaakko J. ; Garton, Daniel R. ; Iivanainen, Vilma H. ; Bhattacharya, Dipabarna ; Jakobsson, Johan LU
; Petteri Piepponen, T.
and Andressoo, Jaan Olle
(2023)
In eNeuro
10(2).
- Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disease that comprises a range of motor and nonmotor symptoms. Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopamine neurons in vitro and in vivo, and intracranial delivery of GDNF has been tested in six clinical trials for treating PD. However, clinical trials with ectopic GDNF have yielded variable results, which could in part result from abnormal expression site and levels caused by ectopic overexpression. Therefore, an important open question is whether an increase in endogenous GDNF expression could be potent in reversing PD progression. Here, we tested the therapeutic potential of endogenous GDNF using mice in which endogenous GDNF can be... (More)
Parkinson’s disease (PD) is a progressive neurodegenerative disease that comprises a range of motor and nonmotor symptoms. Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopamine neurons in vitro and in vivo, and intracranial delivery of GDNF has been tested in six clinical trials for treating PD. However, clinical trials with ectopic GDNF have yielded variable results, which could in part result from abnormal expression site and levels caused by ectopic overexpression. Therefore, an important open question is whether an increase in endogenous GDNF expression could be potent in reversing PD progression. Here, we tested the therapeutic potential of endogenous GDNF using mice in which endogenous GDNF can be conditionally upregulated specifically in cells that express GDNF naturally (conditional GDNF hypermorphic mice; GdnfcHyper). We analyzed the impact of endogenous GDNF upregulation in both neuroprotection and neurorestoration procedures, and for both motor and nonmotor symptoms in the proteasome inhibitor lactacystin (LC) model of PD. Our results showed that upregulation of endogenous GDNF in the adult striatum is not protective in LC-induced PD model in mice. Since age is the largest risk factor for PD, we also analyzed the effect of deletion of endogenous GDNF in aged Gdnf conditional knock-out mice. We found that GDNF deletion does not increase susceptibility to LC-induced damage. We conclude that endogenous GDNF does not impact the outcome in the LC-induced proteasome inhibition mouse model of Parkinson’s disease.
(Less)
- author
- Olfat, Soophie
; Mätlik, Kärt
; Kopra, Jaakko J.
; Garton, Daniel R.
; Iivanainen, Vilma H.
; Bhattacharya, Dipabarna
; Jakobsson, Johan
LU
; Petteri Piepponen, T.
and Andressoo, Jaan Olle
- organization
- publishing date
- 2023-02
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- 39UTR, dopamine, GDNF, mouse model, Parkinson’s disease
- in
- eNeuro
- volume
- 10
- issue
- 2
- article number
- ENEURO.0097-22.2023
- publisher
- Society for Neuroscience
- external identifiers
-
- scopus:85147493465
- pmid:36690469
- ISSN
- 2373-2822
- DOI
- 10.1523/ENEURO.0097-22.2023
- language
- English
- LU publication?
- yes
- id
- a2a4d480-27e1-4f3f-996d-e2e241ca35ac
- date added to LUP
- 2023-02-21 14:24:25
- date last changed
- 2024-06-13 17:23:55
@article{a2a4d480-27e1-4f3f-996d-e2e241ca35ac,
abstract = {{<p>Parkinson’s disease (PD) is a progressive neurodegenerative disease that comprises a range of motor and nonmotor symptoms. Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopamine neurons in vitro and in vivo, and intracranial delivery of GDNF has been tested in six clinical trials for treating PD. However, clinical trials with ectopic GDNF have yielded variable results, which could in part result from abnormal expression site and levels caused by ectopic overexpression. Therefore, an important open question is whether an increase in endogenous GDNF expression could be potent in reversing PD progression. Here, we tested the therapeutic potential of endogenous GDNF using mice in which endogenous GDNF can be conditionally upregulated specifically in cells that express GDNF naturally (conditional GDNF hypermorphic mice; Gdnf<sup>cHyper</sup>). We analyzed the impact of endogenous GDNF upregulation in both neuroprotection and neurorestoration procedures, and for both motor and nonmotor symptoms in the proteasome inhibitor lactacystin (LC) model of PD. Our results showed that upregulation of endogenous GDNF in the adult striatum is not protective in LC-induced PD model in mice. Since age is the largest risk factor for PD, we also analyzed the effect of deletion of endogenous GDNF in aged Gdnf conditional knock-out mice. We found that GDNF deletion does not increase susceptibility to LC-induced damage. We conclude that endogenous GDNF does not impact the outcome in the LC-induced proteasome inhibition mouse model of Parkinson’s disease.</p>}},
author = {{Olfat, Soophie and Mätlik, Kärt and Kopra, Jaakko J. and Garton, Daniel R. and Iivanainen, Vilma H. and Bhattacharya, Dipabarna and Jakobsson, Johan and Petteri Piepponen, T. and Andressoo, Jaan Olle}},
issn = {{2373-2822}},
keywords = {{39UTR; dopamine; GDNF; mouse model; Parkinson’s disease}},
language = {{eng}},
number = {{2}},
publisher = {{Society for Neuroscience}},
series = {{eNeuro}},
title = {{Increased Physiological GDNF Levels Have No Effect on Dopamine Neuron Protection and Restoration in a Proteasome Inhibition Mouse Model of Parkinson’s Disease}},
url = {{http://dx.doi.org/10.1523/ENEURO.0097-22.2023}},
doi = {{10.1523/ENEURO.0097-22.2023}},
volume = {{10}},
year = {{2023}},
}