Journal article 743 views 75 downloads
Alpha-SYNUCLEINOPATHY reduces NMNAT3 protein levels and neurite formation that can be rescued by targeting the NAD+ pathway
,
Altin Kocinaj,
Gustavo Ruiz Pulido,
Sarah A Prendergast,
Anna E Parsons,
Paul Facey ,
Frank Hirth
Human Molecular Genetics, Volume: 31, Issue: 17, Pages: 2918 - 2933
Swansea University Author:
Paul Facey
-
PDF | Version of Record
© The Author(s) 2022.This is an Open Access article distributed under the terms of a Creative Commons Attribution CC BY licence.
Download (1.61MB)
DOI (Published version): 10.1093/hmg/ddac077
Abstract
Parkinson’s disease is characterised by the deposition of α-synuclein, which leads to synaptic dysfunction, the loss of neuronal connections and ultimately progressive neurodegeneration. Despite extensive research into Parkinson’s disease pathogenesis, the mechanisms underlying α-synuclein mediated...
| Published in: | Human Molecular Genetics |
|---|---|
| ISSN: | 0964-6906 1460-2083 |
| Published: |
Oxford University Press (OUP)
2022
|
| Online Access: |
Check full text
|
| URI: | https://cronfa.swan.ac.uk/Record/cronfa59792 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Abstract: |
Parkinson’s disease is characterised by the deposition of α-synuclein, which leads to synaptic dysfunction, the loss of neuronal connections and ultimately progressive neurodegeneration. Despite extensive research into Parkinson’s disease pathogenesis, the mechanisms underlying α-synuclein mediated synaptopathy have remained elusive. Several lines of evidence suggest that altered NAD+ metabolism might be causally related to synucleinopathies, including Parkinson’s disease. NAD+ metabolism is central to the maintenance of synaptic structure and function. Its synthesis is mediated by nicotinamide mononucleotide adenylyltransferases (NMNATs), but their role in Parkinson’s disease is not known. Here we report significantly decreased levels of NMNAT3 protein in the caudate nucleus of patients who have died with Parkinson’s disease which inversely correlated with the amount of monomeric α-synuclein. The detected alterations were specific and significant as the expression levels of NMNAT1, NMNAT2 and sterile alpha and TIR motif containing 1 were not significantly different in Parkinson’s disease subjects compared to controls. To test the functional significance of these findings, we ectopically expressed wild-type α-synuclein in retinoic acid-differentiated dopaminergic SH-SY5Y cells which resulted in decreased levels of NMNAT3 protein plus a neurite pathology which could be rescued by FK866, an inhibitor of nicotinamide phosphoribosyltransferase that acts as a key enzyme in the regulation of NAD+ synthesis. Our results establish, for the first time, NMNAT3 alterations in Parkinson’s disease and demonstrate in human cells that this phenotype together with neurite pathology is causally related to α-synucleinopathy. These findings identify alterations in the NAD+ biosynthetic pathway as a pathogenic mechanism underlying α-synuclein mediated synaptopathy. |
|---|---|
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
This study was funded by The Dunhill Medical Trust grant reference R561/0271 to F.H. and
R.B.P. The Dunhill Medical Trust played no part in the design, implementation, analysis and
writing of the manuscript and were not involved in the decision to publish. Frozen tissue
samples and associated clinical and neuropathological data were supplied by the Parkinson’s
UK Brain Bank, funded by Parkinson’s UK, a charity registered in England and Wales
(258197) and in Scotland (SC037554). The Queen Square Brain Bank is supported by the
Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of
Neurology. We thank the Nikon Imaging Centre at King’s College London and Isma Ali for
help with confocal microscopy and image analysis. |
| Issue: |
17 |
| Start Page: |
2918 |
| End Page: |
2933 |