Evidence map›Paper›PMID 27499521›Full record

ArticleAmerican journal of human genetics2016

The Power of Human Protective Modifiers: PLS3 and CORO1C Unravel Impaired Endocytosis in Spinal Muscular Atrophy and Rescue SMA Phenotype.

Seyyedmohsen Hosseinibarkooie, Miriam Peters, Laura Torres-Benito, Raphael H Rastetter, Kristina Hupperich, Andrea Hoffmann, Natalia Mendoza-Ferreira, Anna Kaczmarek, Eva Janzen, Janine Milbradt and 10 more

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

Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
100citing papers in PubMed, 3 pooled it
14.3field-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

100 citing papers in PubMed, 3 syntheses or guidelines pooled it, 165 citations in OpenAlex.

  1. Pooled it
  2. Drug treatment for spinal muscular atrophy types II and III.The Cochrane database of systematic reviews · 2020
    Pooled it
  3. Drug treatment for spinal muscular atrophy type I.The Cochrane database of systematic reviews · 2019
    Pooled it
  4. Trial
  5. Article
  6. Article
  7. Review
  8. Review
  9. Review
  10. Review
  11. [Research progress on phenotypic modifier genes in spinal muscular atrophy].Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2025
    Review
  12. Article
  13. Article
  14. Review
  15. Patient-specific responses toMolecular therapy. Methods & clinical development · 2024
    Article
  16. In Search of Spinal Muscular Atrophy Disease Modifiers.International journal of molecular sciences · 2024
    Review
  17. Article
  18. Article
  19. Article
  20. Review

40 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

20 authors at 3 institutions in 2 countries.

Seyyedmohsen HosseinibarkooieInstitute of Human Genetics, University of Cologne, 50931 Cologne Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
Miriam PetersInstitute of Human Genetics, University of Cologne, 50931 Cologne Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
Laura Torres-BenitoInstitute of Human Genetics, University of Cologne, 50931 Cologne Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
Raphael H RastetterCenter for Biochemistry, Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
Kristina HupperichInstitute of Human Genetics, University of Cologne, 50931 Cologne Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
Andrea HoffmannInstitute of Human Genetics, University of Cologne, 50931 Cologne Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
Natalia Mendoza-FerreiraInstitute of Human Genetics, University of Cologne, 50931 Cologne Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
Anna KaczmarekInstitute of Human Genetics, University of Cologne, 50931 Cologne Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
Eva JanzenInstitute of Human Genetics, University of Cologne, 50931 Cologne Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
Janine MilbradtInstitute of Human Genetics, University of Cologne, 50931 Cologne Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
Tobias LamkemeyerCologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
Frank RigoIONIS Pharmaceuticals, 2855 Carlsbad, CA 92008, USA.
C Frank BennettIONIS Pharmaceuticals, 2855 Carlsbad, CA 92008, USA.
Christoph GuschlbauerBiocenter, Institute for Zoology, Neurophysiology, University of Cologne, 50674 Cologne, Germany.
Ansgar BüschgesBiocenter, Institute for Zoology, Neurophysiology, University of Cologne, 50674 Cologne, Germany.
Matthias HammerschmidtCenter for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Biocenter, Institute for Zoology, Developmental Biology, University of Cologne, 50674 Cologne, Germany.
Markus RiesslandInstitute of Human Genetics, University of Cologne, 50931 Cologne Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
Min Jeong KyeInstitute of Human Genetics, University of Cologne, 50931 Cologne Germany.
Christoph S ClemenCenter for Biochemistry, Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
Brunhilde WirthInstitute of Human Genetics, University of Cologne, 50931 Cologne Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany. Electronic address: brunhilde.wirth@uk-koeln.de.
University of Cologne · DEIonis Pharmaceuticals (United States) · USCologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases · DE

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Homozygous loss of SMN1 causes spinal muscular atrophy (SMA), the most common and devastating childhood genetic motor-neuron disease. The copy gene SMN2 produces only ∼10% functional SMN protein, insufficient to counteract development of SMA. In contrast, the human genetic modifier plastin 3 (PLS3), an actin-binding and -bundling protein, fully protects against SMA in SMN1-deleted individuals carrying 3-4 SMN2 copies. Here, we demonstrate that the combinatorial effect of suboptimal SMN antisense oligonucleotide treatment and PLS3 overexpression-a situation resembling the human condition in asymptomatic SMN1-deleted individuals-rescues survival (from 14 to >250 days) and motoric abilities in a severe SMA mouse model. Because PLS3 knockout in yeast impairs endocytosis, we hypothesized that disturbed endocytosis might be a key cellular mechanism underlying impaired neurotransmission and neuromuscular junction maintenance in SMA. Indeed, SMN deficit dramatically reduced endocytosis, which was restored to normal levels by PLS3 overexpression. Upon low-frequency electro-stimulation, endocytotic FM1-43 (SynaptoGreen) uptake in the presynaptic terminal of neuromuscular junctions was restored to control levels in SMA-PLS3 mice. Moreover, proteomics and biochemical analysis revealed CORO1C, another F-actin binding protein, whose direct binding to PLS3 is dependent on calcium. Similar to PLS3 overexpression, CORO1C overexpression restored fluid-phase endocytosis in SMN-knockdown cells by elevating F-actin amounts and rescued the axonal truncation and branching phenotype in Smn-depleted zebrafish. Our findings emphasize the power of genetic modifiers to unravel the cellular pathomechanisms underlying SMA and the power of combinatorial therapy based on splice correction of SMN2 and endocytosis improvement to efficiently treat SMA.

Indexed as

ActinsAnimalsAxonsCalciumCarrier ProteinsDisease Models, AnimalEndocytosisHumansMaleMembrane GlycoproteinsMiceMicrofilament ProteinsMuscular Atrophy, SpinalNeuromuscular JunctionOligonucleotides, AntisensePhenotypeActinsCalciumCarrier Proteinscoronin proteinsF-actin-binding proteinsFM1 43Membrane GlycoproteinsMicrofilament ProteinsOligonucleotides, AntisenseplastinPyridinium CompoundsQuaternary Ammonium CompoundsSMN1 protein, humanSMN2 protein, humanSurvival of Motor Neuron 1 ProteinSurvival of Motor Neuron 2 Protein

Identifiers

PMID27499521
PMCPMC5011078
OpenAlexW2477368596

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.