Evidence map›Paper›PMID 31319154›Full record

ArticleBiochimica et biophysica acta. Molecular basis of disease2019

The molecular tweezer CLR01 reduces aggregated, pathologic, and seeding-competent α-synuclein in experimental multiple system atrophy.

Marcos Herrera-Vaquero, Danielle Bouquio, Martin Kallab, Karl Biggs, Gayatri Nair, Jessica Ochoa, Antonio Heras-Garvin, Christian Heid, Inesa Hadrovic, Werner Poewe and 5 more

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

Article in Biochimica et biophysica acta. Molecular basis of disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.

0numbers the graph read from it
0cells of the map it votes in
21citing papers in PubMed
3.4field-weighted citation impact, top 7% 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

21 citing papers in PubMed, 33 citations in OpenAlex.

  1. Multiple system atrophy: cure and care.Journal of neural transmission (Vienna, Austria : 1996) · 2026
    Review
  2. Article
  3. Article
  4. Review
  5. Article
  6. Recent Advances in Clinical Trials in Multiple System Atrophy.Current neurology and neuroscience reports · 2024
    Review
  7. Article
  8. Review
  9. Review
  10. A Mouse Model of Multiple System Atrophy: Bench to Bedside.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023
    Review
  11. Three-repeat and four-repeat tau isoforms form different oligomers.Protein science : a publication of the Protein Society · 2022
    Article
  12. Article
  13. Review
  14. Current experimental disease-modifying therapeutics for multiple system atrophy.Journal of neural transmission (Vienna, Austria : 1996) · 2021
    Review
  15. Article
  16. Article
  17. Review
  18. Current Management and Emerging Therapies in Multiple System Atrophy.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2020
    Review
  19. Article
  20. Article
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

15 authors at 3 institutions in 3 countries.

Marcos Herrera-VaqueroDivision of Neurobiology, Department of Neurology, Medical University of Innsbruck, Austria.
Danielle BouquioDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Martin KallabDivision of Neurobiology, Department of Neurology, Medical University of Innsbruck, Austria.
Karl BiggsDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Gayatri NairDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Jessica OchoaDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Brain Research Institute and Molecular Biology Institute, University of California, Los Angeles, CA, USA.
Antonio Heras-GarvinDivision of Neurobiology, Department of Neurology, Medical University of Innsbruck, Austria.
Christian HeidInstitute of Chemistry, University of Duisburg-Essen, Essen, Germany.
Inesa HadrovicInstitute of Chemistry, University of Duisburg-Essen, Essen, Germany.
Werner PoeweDivision of Neurobiology, Department of Neurology, Medical University of Innsbruck, Austria.
Gregor K WenningDivision of Neurobiology, Department of Neurology, Medical University of Innsbruck, Austria.
Frank-Gerrit KlärnerInstitute of Chemistry, University of Duisburg-Essen, Essen, Germany.
Thomas SchraderInstitute of Chemistry, University of Duisburg-Essen, Essen, Germany.
Gal BitanDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Brain Research Institute and Molecular Biology Institute, University of California, Los Angeles, CA, USA. Electronic address: gbitan@mednet.ucla.edu.
Nadia StefanovaDivision of Neurobiology, Department of Neurology, Medical University of Innsbruck, Austria. Electronic address: nadia.stefanova@i-med.ac.at.
Innsbruck Medical University · ATUniversity of California, Los Angeles · USUniversity of Duisburg-Essen · DE

Funding

Women's CancersP30CA016042 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Samuel Wheeler French · 1985 to 2026
$134.5M
UCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1M
Virology CoreP30AI028697 · NIAID · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI KITCHEN, SCOTT G · 1991 to 2018
$39.9M
Misfolded protein-clearance enhancers for Alzheimer's therapyR01AG050721 · NIA · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI BITAN, GAL · 2015 to 2019
$2.0M
Austrian Science Fund FWF I 2102NCATS NIH HHS UL1 TR001881NCI NIH HHS P30 CA016042NIAID NIH HHS P30 AI028697NIA NIH HHS R01 AG050721
6 · The paper itself

Abstract

Multiple system atrophy (MSA) is a fatal, adult-onset neurodegenerative disorder that has no cure and very limited treatment options. MSA is characterized by deposition of fibrillar α-synuclein (α-syn) in glial cytoplasmic inclusions in oligodendrocytes. Similar to other synucleinopathies, α-syn self-assembly is thought to be a key pathologic event and a prominent target for disease modification in MSA. Molecular tweezers are broad-spectrum nanochaperones that prevent formation of toxic protein assemblies and enhance their clearance. The current lead compound, CLR01, has been shown to inhibit α-syn aggregation but has not yet been tested in the context of MSA. To fill this gap, here, we conducted a proof-of-concept study to assess the efficacy of CLR01 in remodeling MSA-like α-syn pathology in the PLP-α-syn mouse model of MSA. Six-month-old mice received intracerebroventricular CLR01 (0.3 or 1 mg/kg per day) or vehicle for 32 days. Open-field test revealed a significant, dose-dependent amelioration of an anxiety-like phenotype. Subsequently, immunohistochemical and biochemical analyses showed dose-dependent reduction of pathological and seeding-competent forms of α-syn, which correlated with the behavioral phenotype. CLR01 treatment also promoted dopaminergic neuron survival in the substantia nigra. To our knowledge, this is the first demonstration of an agent that reduces formation of putative high-molecular-weight oligomers and seeding-competent α-syn in a mouse model of MSA, supporting the view that these species are key to the neurodegenerative process and its cell-to-cell progression in MSA. Our study suggests that CLR01 is an attractive therapeutic candidate for disease modification in MSA and related synucleinopathies, supporting further preclinical development.

Indexed as

alpha-SynucleinAnimalsBrainBridged-Ring CompoundsCell LineDisease Models, AnimalDopaminergic NeuronsHumansMaleMiceMultiple System AtrophyNeuroprotective AgentsOrganophosphatesProtein Aggregation, Pathologicalalpha-SynucleinBridged-Ring CompoundsCLR01 compoundNeuroprotective AgentsOrganophosphatesAggregationGlial cytoplasmic inclusionsMouse modelMultiple system atrophyNeuropathologyOligomersationSeedingSynucleinopathy

Identifiers

PMID31319154
PMCPMC8425273
OpenAlexW2960101908

What OpenQuestion holds

Textmetadata
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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.