Evidence map›Paper›PMID 36646701›Full record

ArticleNPJ Parkinson's disease2023

Dynamic physiological α-synuclein S129 phosphorylation is driven by neuronal activity.

Nagendran Ramalingam, Shan-Xue Jin, Tim E Moors, Luis Fonseca-Ornelas, Kazuma Shimanaka, Shi Lei, Hugh P Cam, Aurelia Hays Watson, Lisa Brontesi, Lai Ding and 13 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in NPJ Parkinson's disease, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.

0numbers the graph read from it
0cells of the map it votes in
92citing papers in PubMed
27.6field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

92 citing papers in PubMed, 134 citations in OpenAlex.

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32 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors at 4 institutions in 2 countries.

Nagendran RamalingamAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA. nramalingam@bwh.harvard.edu.ORCID http://orcid.org/0000-0002-9459-3593
Shan-Xue Jin *Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Tim E Moors *Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Luis Fonseca-OrnelasAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.ORCID http://orcid.org/0000-0001-7810-5564
Kazuma ShimanakaAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Shi LeiLeveragen, Inc., 17 Briden Street, Worcester, MA, 01605, USA.
Hugh P CamLeveragen, Inc., 17 Briden Street, Worcester, MA, 01605, USA.
Aurelia Hays WatsonUK Dementia Research Institute, University College London, London, UK.
Lisa BrontesiAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Lai DingAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Dinc Yasat HacibalogluAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Haiyang JiangAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.ORCID http://orcid.org/0000-0003-0192-3889
Se Joon ChoiDivision of Molecular Therapeutics, New York State Psychiatric Institute, Research Foundation for Mental Hygiene, New York, NY, 10032, USA.
Ellen KanterDivision of Molecular Therapeutics, New York State Psychiatric Institute, Research Foundation for Mental Hygiene, New York, NY, 10032, USA.
Lei LiuAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.ORCID http://orcid.org/0000-0002-4604-4629
Tim BartelsUK Dementia Research Institute, University College London, London, UK.
Silke NuberAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
David SulzerDivision of Molecular Therapeutics, New York State Psychiatric Institute, Research Foundation for Mental Hygiene, New York, NY, 10032, USA.ORCID http://orcid.org/0000-0001-7632-0439
Eugene V MosharovDivision of Molecular Therapeutics, New York State Psychiatric Institute, Research Foundation for Mental Hygiene, New York, NY, 10032, USA.ORCID http://orcid.org/0000-0002-0229-7114
Weisheng V ChenLeveragen, Inc., 17 Briden Street, Worcester, MA, 01605, USA.
Shaomin LiAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.ORCID http://orcid.org/0000-0001-9451-2151
Dennis J SelkoeAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.ORCID http://orcid.org/0000-0001-8846-9767
Ulf DettmerAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA. udettmer@bwh.harvard.edu.ORCID http://orcid.org/0000-0001-6676-0107
Brigham and Women's Hospital · USColumbia University Irving Medical Center · USResearch Foundation For Mental Hygiene · USUK Dementia Research Institute · GB

Funding

The Dopamine Synapse and Associative LearningR01DA007418 · NIDA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI David Sulzer · 1999 to 2026
$9.4M
Autoimmune Features of Neurodegenerative DisordersR01NS095435 · NINDS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI SETTE, ALESSANDRO, SULZER, DAVID · 2018 to 2022
$4.2M
Biology of Native Alpha-Synuclein Tetramers in Parkinson's DiseaseRF1NS083845 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI SELKOE, DENNIS J · 2020 to 2020
$2.9M
Polo-like-kinase-2-dependent α-Synuclein Serine-129 Phosphorylation: a Physiological RoleDuring Synaptic ActivityRF1NS122880 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI DETTMER, ULF, RAMALINGAM, NAGENDRAN · 2022 to 2022
$2.1M
Stabilizing native α-synuclein homeostasis to prevent insoluble α-synuclein aggregatesR01NS099328 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI DETTMER, ULF · 2017 to 2021
$1.9M
Biologically novel mouse models of PD with progressive synucleinopathy and early-onset tremor and motor deficits responsive to L-DOPAR01NS109510 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI NUBER, SILKE · 2019 to 2023
$1.9M
NIDA NIH HHS R01 DA007418NINDS NIH HHS R01 NS095435NINDS NIH HHS R01 NS099328NINDS NIH HHS R01 NS109510NINDS NIH HHS RF1 NS083845
6 · The paper itself

Abstract

In Parkinson's disease and other synucleinopathies, the elevation of α-synuclein phosphorylated at Serine129 (pS129) is a widely cited marker of pathology. However, the physiological role for pS129 has remained undefined. Here we use multiple approaches to show for the first time that pS129 functions as a physiological regulator of neuronal activity. Neuronal activity triggers a sustained increase of pS129 in cultured neurons (200% within 4 h). In accord, brain pS129 is elevated in environmentally enriched mice exhibiting enhanced long-term potentiation. Activity-dependent α-synuclein phosphorylation is S129-specific, reversible, confers no cytotoxicity, and accumulates at synapsin-containing presynaptic boutons. Mechanistically, our findings are consistent with a model in which neuronal stimulation enhances Plk2 kinase activity via a calcium/calcineurin pathway to counteract PP2A phosphatase activity for efficient phosphorylation of membrane-bound α-synuclein. Patch clamping of rat SNCA

Identifiers

PMID36646701
PMCPMC9842642
OpenAlexW4316511422

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.