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GDNF Therapy: Can We Make It Work?

In two recent postmortem studies, Jeffrey Kordower and colleagues report new findings that open up for an interesting discussion on the status of GDNF/NRTN signaling in patients with Parkinson’s disease (PD), adding an interesting perspective on the, admittedly very limited, signs of restorative eff...

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Autor principal: Björklund, Anders
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9789476/
https://www.ncbi.nlm.nih.gov/pubmed/33935108
http://dx.doi.org/10.3233/JPD-212706
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author Björklund, Anders
author_facet Björklund, Anders
author_sort Björklund, Anders
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description In two recent postmortem studies, Jeffrey Kordower and colleagues report new findings that open up for an interesting discussion on the status of GDNF/NRTN signaling in patients with Parkinson’s disease (PD), adding an interesting perspective on the, admittedly very limited, signs of restorative effects previously seen in GDNF/NRTN-treated patients. Their new findings show that the level of the GDNF signaling receptor Ret is overall markedly reduced relative to the non-PD controls, and most severely, up to 80%, in nigral neurons containing α-synuclein inclusions, accompanied by impaired signaling downstream of the Ret receptor. Notably, however, the vast majority of the remaining nigral neurons retained a low level of Ret expression, and hence a threshold level of signaling. Further observations made in two patients who had received AAV-NRTN gene therapy 8–10 years earlier suggest the intriguing possibility that NRTN is able to restore Ret expression and upregulate its own signaling pathway. This “wind-up” mechanism, which is likely to depend on an interaction with dopaminergic transcription factor Nurr1, has therapeutic potential and should encourage renewed efforts to turn GDNF/NRTN therapy into success, once the recurring problem of under-dosing is resolved.
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spelling pubmed-97894762023-01-17 GDNF Therapy: Can We Make It Work? Björklund, Anders J Parkinsons Dis Commentary In two recent postmortem studies, Jeffrey Kordower and colleagues report new findings that open up for an interesting discussion on the status of GDNF/NRTN signaling in patients with Parkinson’s disease (PD), adding an interesting perspective on the, admittedly very limited, signs of restorative effects previously seen in GDNF/NRTN-treated patients. Their new findings show that the level of the GDNF signaling receptor Ret is overall markedly reduced relative to the non-PD controls, and most severely, up to 80%, in nigral neurons containing α-synuclein inclusions, accompanied by impaired signaling downstream of the Ret receptor. Notably, however, the vast majority of the remaining nigral neurons retained a low level of Ret expression, and hence a threshold level of signaling. Further observations made in two patients who had received AAV-NRTN gene therapy 8–10 years earlier suggest the intriguing possibility that NRTN is able to restore Ret expression and upregulate its own signaling pathway. This “wind-up” mechanism, which is likely to depend on an interaction with dopaminergic transcription factor Nurr1, has therapeutic potential and should encourage renewed efforts to turn GDNF/NRTN therapy into success, once the recurring problem of under-dosing is resolved. IOS Press 2021-08-02 /pmc/articles/PMC9789476/ /pubmed/33935108 http://dx.doi.org/10.3233/JPD-212706 Text en © 2021 – The authors. Published by IOS Press https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Commentary
Björklund, Anders
GDNF Therapy: Can We Make It Work?
title GDNF Therapy: Can We Make It Work?
title_full GDNF Therapy: Can We Make It Work?
title_fullStr GDNF Therapy: Can We Make It Work?
title_full_unstemmed GDNF Therapy: Can We Make It Work?
title_short GDNF Therapy: Can We Make It Work?
title_sort gdnf therapy: can we make it work?
topic Commentary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9789476/
https://www.ncbi.nlm.nih.gov/pubmed/33935108
http://dx.doi.org/10.3233/JPD-212706
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