Evidence map›Paper›PMID 25363075›Full record

ArticleAnnals of neurology2015

Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization.

Judith Eschbach, Björn von Einem, Kathrin Müller, Hanna Bayer, Annika Scheffold, Bradley E Morrison, K Lenhard Rudolph, Dietmar R Thal, Anke Witting, Patrick Weydt and 8 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Annals of neurology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
67citing papers in PubMed, 1 pooled it
4.3field-weighted citation impact, top 5% 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

67 citing papers in PubMed, 1 synthesis or guideline pooled it, 126 citations in OpenAlex.

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7 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

18 authors at 5 institutions in 2 countries.

Judith EschbachDepartment of Neurology, Ulm University, Ulm, Germany; Inoviem Scientific, Strasbourg, France.
Björn von Einem
Kathrin Müller
Hanna Bayer
Annika Scheffold
Bradley E Morrison
K Lenhard Rudolph
Dietmar R Thal
Anke Witting
Patrick Weydt
Markus Otto
Michael Fauler
Birgit Liss
Pamela J McLean
Albert R La Spada
Albert C Ludolph
Jochen H Weishaupt
Karin M Danzer
Universität Ulm · DETechnische Hochschule Ulm · DEUniversity of California, San Diego · USLeibniz Association · DEWinnMed · US

Funding

The PPAR-delta pathway in neural function and Huntington's disease neuropathologyR01NS065874 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI LA SPADA, ALBERT R · 2010 to 2020
$4.0M
Extracellular alpha-synuclein in Parkinson's DiseaseR01NS073740 · NINDS · MAYO CLINIC JACKSONVILLE · PI MCLEAN, PAMELA J · 2011 to 2015
$1.7M
NINDS NIH HHS R01 NS065874NINDS NIH HHS R01 NS073740NINDS NIH HHS R01-NS073740
6 · The paper itself

Abstract

objectiveAggregation of α-synuclein (α-syn) and α-syn cytotoxicity are hallmarks of sporadic and familial Parkinson disease (PD), with accumulating evidence that prefibrillar oligomers and protofibrils are the pathogenic species in PD and related synucleinopathies. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a key regulator of mitochondrial biogenesis and cellular energy metabolism, has recently been associated with the pathophysiology of PD. Despite extensive effort on studying the function of PGC-1α in mitochondria, no studies have addressed whether PGC-1α directly influences oligomerization of α-syn or whether α-syn oligomers impact PGC-1α expression. MATERIALS AND

methodsWe tested whether pharmacological or genetic activation of PGC-1α or PGC-11α knockdown could modulate the oligomerization of α-syn in vitro by using an α-syn -fragment complementation assay.

resultsIn this study, we found that both PGC-1α reference gene (RG-PGC-1α) and the central nervous system (CNS)-specific PGC-1α (CNS-PGC-1α) are downregulated in human PD brain, in A30P α-syn transgenic animals, and in a cell culture model for α-syn oligomerization. Importantly, downregulation of both RG-PGC-1α and CNS-PGC-1α in cell culture or neurons from RG-PGC-1α-deficient mice leads to a strong induction of α-syn oligomerization and toxicity. In contrast, pharmacological activation or genetic overexpression of RG-PGC-1α reduced α-syn oligomerization and rescued α-syn-mediated toxicity.

interpretationBased on our results, we propose that PGC-1α downregulation and α-syn oligomerization form a vicious circle, thereby influencing and/or potentiating each other. Our data indicate that restoration of PGC-1α is a promising approach for development of effective drugs for the treatment of PD and related synucleinopathies.

Indexed as

AgedAged, 80 and overalpha-SynucleinAnimalsCells, CulturedCerebral CortexDisease Models, AnimalEmbryo, MammalianEnzyme InhibitorsFemaleGene Expression RegulationGliomaHumansMacrolidesMaleMicealpha-Synucleinbafilomycin A1Enzyme InhibitorsMacrolidesPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaPPAR gammaPpargc1a protein, mouseResveratrolRNA Polymerase IIStilbenesTATA-Box Binding ProteinTranscription Factors

Identifiers

PMID25363075
PMCPMC4293280
OpenAlexW1505478984

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

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.