GDNF Therapy : Can We Make It Work?
Björklund, Anders LU
(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.
(Less)
- 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
-
- pmid:33935108
- scopus:85112230503
- 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
- 2024-06-01 13:12:41
@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}},
}