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Alpha-SYNUCLEINOPATHY reduces NMNAT3 protein levels and neurite formation that can be rescued by targeting the NAD+ pathway

Richard B Parsons Orcid Logo, Altin Kocinaj, Gustavo Ruiz Pulido, Sarah A Prendergast, Anna E Parsons, Paul Facey Orcid Logo, Frank Hirth

Human Molecular Genetics, Volume: 31, Issue: 17, Pages: 2918 - 2933

Swansea University Author: Paul Facey Orcid Logo

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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...

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Published in: Human Molecular Genetics
ISSN: 0964-6906 1460-2083
Published: Oxford University Press (OUP) 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa59792
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Several lines of evidence suggest that altered NAD+ metabolism might be causally related to synucleinopathies, including Parkinson&#x2019;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&#x2019;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&#x2019;s disease which inversely correlated with the amount of monomeric &#x3B1;-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&#x2019;s disease subjects compared to controls. To test the functional significance of these findings, we ectopically expressed wild-type &#x3B1;-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&#x2019;s disease and demonstrate in human cells that this phenotype together with neurite pathology is causally related to &#x3B1;-synucleinopathy. 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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&#x2019;s UK Brain Bank, funded by Parkinson&#x2019;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. 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spelling 2023-01-04T11:54:00.4482680 v2 59792 2022-04-11 Alpha-SYNUCLEINOPATHY reduces NMNAT3 protein levels and neurite formation that can be rescued by targeting the NAD+ pathway dc25910b8004b2694df68ed7426e1286 0000-0002-3229-0255 Paul Facey Paul Facey true false 2022-04-11 BMS 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. Journal Article Human Molecular Genetics 31 17 2918 2933 Oxford University Press (OUP) 0964-6906 1460-2083 9 4 2022 2022-04-09 10.1093/hmg/ddac077 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee 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. The Dunhill Medical Trust grant reference R561/0271 2023-01-04T11:54:00.4482680 2022-04-11T12:17:25.6844896 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Richard B Parsons 0000-0001-5618-3780 1 Altin Kocinaj 2 Gustavo Ruiz Pulido 3 Sarah A Prendergast 4 Anna E Parsons 5 Paul Facey 0000-0002-3229-0255 6 Frank Hirth 7 59792__24323__d92c290b39dd4e4a8b779e460aa66817.pdf 59792.Corrected proof.pdf 2022-06-15T17:01:15.1913168 Output 1686757 application/pdf Version of Record true © The Author(s) 2022.This is an Open Access article distributed under the terms of a Creative Commons Attribution CC BY licence. true eng http://creativecommons.org/licenses/by/4.0/
title Alpha-SYNUCLEINOPATHY reduces NMNAT3 protein levels and neurite formation that can be rescued by targeting the NAD+ pathway
spellingShingle Alpha-SYNUCLEINOPATHY reduces NMNAT3 protein levels and neurite formation that can be rescued by targeting the NAD+ pathway
Paul Facey
title_short Alpha-SYNUCLEINOPATHY reduces NMNAT3 protein levels and neurite formation that can be rescued by targeting the NAD+ pathway
title_full Alpha-SYNUCLEINOPATHY reduces NMNAT3 protein levels and neurite formation that can be rescued by targeting the NAD+ pathway
title_fullStr Alpha-SYNUCLEINOPATHY reduces NMNAT3 protein levels and neurite formation that can be rescued by targeting the NAD+ pathway
title_full_unstemmed Alpha-SYNUCLEINOPATHY reduces NMNAT3 protein levels and neurite formation that can be rescued by targeting the NAD+ pathway
title_sort Alpha-SYNUCLEINOPATHY reduces NMNAT3 protein levels and neurite formation that can be rescued by targeting the NAD+ pathway
author_id_str_mv dc25910b8004b2694df68ed7426e1286
author_id_fullname_str_mv dc25910b8004b2694df68ed7426e1286_***_Paul Facey
author Paul Facey
author2 Richard B Parsons
Altin Kocinaj
Gustavo Ruiz Pulido
Sarah A Prendergast
Anna E Parsons
Paul Facey
Frank Hirth
format Journal article
container_title Human Molecular Genetics
container_volume 31
container_issue 17
container_start_page 2918
publishDate 2022
institution Swansea University
issn 0964-6906
1460-2083
doi_str_mv 10.1093/hmg/ddac077
publisher Oxford University Press (OUP)
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description 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.
published_date 2022-04-09T04:17:21Z
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