Evidence map›Paper›PMID 36951087›Full record

ArticleDisease models & mechanisms2023

Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency.

Marcus Keatinge, Matthew E Gegg, Lisa Watson, Heather Mortiboys, Nan Li, Mark Dunning, Deepak Ailani, Hai Bui, Astrid van Rens, Dirk J Lefeber and 3 more

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

Article in Disease models & mechanisms, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
0.7field-weighted citation impact, top 31% 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

3 citing papers in PubMed, 4 citations in OpenAlex.

  1. Article
  2. C9ORF72 Deficiency Results in Neurodegeneration in the Zebrafish Retina.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024
    Article
  3. 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

13 authors at 4 institutions in 3 countries.

Marcus KeatingeBateson Centre, Firth Court, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.ORCID 0000-0003-2055-1187
Matthew E GeggDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London NW3 2PF, UK.
Lisa WatsonBateson Centre, Firth Court, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
Heather MortiboysSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield S10 2HQ, UK.
Nan LiBateson Centre, Firth Court, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
Mark DunningSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield S10 2HQ, UK.
Deepak AilaniBateson Centre, Firth Court, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
Hai BuiEli Lilly and Company, Drop Code 1940, Indianapolis, IN 46285, USA.
Astrid van RensDepartment of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen NL-6525 GA, The Netherlands.
Dirk J LefeberDepartment of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen NL-6525 GA, The Netherlands.
Anthony H V SchapiraDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London NW3 2PF, UK.
Ryan B MacDonaldBateson Centre, Firth Court, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.ORCID 0000-0003-4194-8925
Oliver BandmannBateson Centre, Firth Court, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.ORCID 0000-0003-3149-0252
University of Sheffield · GBNational Hospital for Neurology and Neurosurgery · GBRadboud University Nijmegen · NLEli Lilly (United States) · US

Funding

Medical Research Council MR/M006646/1Medical Research Council MR/R011354/1Parkinson's UK G-1704
6 · The paper itself

Abstract

Heterozygous variants in GBA1, encoding glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants of SMPD1 are also overrepresented in PD cohorts, whereas a reduction of its encoded enzyme (acid sphingomyelinase or ASM) activity is linked to an earlier age of PD onset. Despite both converging on the ceramide pathway, how the combined deficiencies of both enzymes might interact to modulate PD has yet to be explored. Therefore, we created a double-knockout (DKO) zebrafish line for both gba1 (or gba) and smpd1 to test for an interaction in vivo, hypothesising an exacerbation of phenotypes in the DKO line compared to those for single mutants. Unexpectedly, DKO zebrafish maintained conventional swimming behaviour and had normalised neuronal gene expression signatures compared to those of single mutants. We further identified rescue of mitochondrial Complexes I and IV in DKO zebrafish. Despite having an unexpected rescue effect, our results confirm ASM as a modifier of GBA1 deficiency in vivo. Our study highlights the need for validating how genetic variants and enzymatic deficiencies may interact in vivo.

Indexed as

Niemann-Pick Disease, Type AParkinson Diseasealpha-SynucleinAnimalsGlucosylceramidaseMutationPhenotypeZebrafishalpha-SynucleinGlucosylceramidaseAcid sphingomyelinaseGene-gene interactionGlucocerebrosidase 1Parkinson's diseaseZebrafish

Identifiers

PMID36951087
PMCPMC10184672
OpenAlexW4360600621

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.