GDNF Therapy : Can We Make It Work?
(2021) In Journal of Parkinson's Disease 11(3). p.1019-1022- Abstract
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 reduced by about 65% relative to 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,... (More)
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 reduced by about 65% relative to 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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- author
- Björklund, Anders LU
- organization
- publishing date
- 2021-08-02
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Parkinson's Disease
- volume
- 11
- issue
- 3
- pages
- 4 pages
- publisher
- IOS Press
- external identifiers
-
- scopus:85112230503
- pmid:33935108
- ISSN
- 1877-718X
- DOI
- 10.3233/JPD-212706
- language
- English
- LU publication?
- yes
- id
- 15255500-9dae-4e08-a7ef-2c96cc3d067f
- date added to LUP
- 2021-08-03 16:26:16
- date last changed
- 2024-08-24 20:45:37
@article{15255500-9dae-4e08-a7ef-2c96cc3d067f, abstract = {{<p>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 reduced by about 65% relative to 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.</p>}}, author = {{Björklund, Anders}}, issn = {{1877-718X}}, language = {{eng}}, month = {{08}}, number = {{3}}, pages = {{1019--1022}}, publisher = {{IOS Press}}, series = {{Journal of Parkinson's Disease}}, title = {{GDNF Therapy : Can We Make It Work?}}, url = {{http://dx.doi.org/10.3233/JPD-212706}}, doi = {{10.3233/JPD-212706}}, volume = {{11}}, year = {{2021}}, }