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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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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
IOS Press
2021
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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 |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-9789476 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | IOS Press |
record_format | MEDLINE/PubMed |
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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