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

Keatinge, Marcus; Gegg, Matthew E; Watson, Lisa; Mortiboys, Heather; Li, Nan; Dunning, Mark; Ailani, Deepak; ... Bandmann, Oliver; + view all (2023) Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency. Disease Models & Mechanisms 10.1242/dmm.049954. (In press). Green open access

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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 in SMPD1 are also overrepresented in PD cohorts, whilst a reduction of its encoded enzyme (ASM) activity is linked to an earlier age of PD onset. Despite both converging on the ceramide pathway, how combined deficiencies of both enzymes may interact to modulate PD has yet to be explored. Therefore, we created a double knock out (DKO) zebrafish line for both gba1 and smpd1 to test for an interaction in vivo, hypothesising an exacerbation of phenotypes in the DKO compared to single mutants. Unexpectedly, DKOs maintained conventional swimming behaviour and had normalised neuronal gene expression signatures when compared to single mutants. We further identified rescue of mitochondrial Complexes I and IV in DKOs. 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.

Type: Article
Title: Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/dmm.049954
Publisher version: https://doi.org/10.1242/dmm.049954
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Acid sphingomyelinase, Gene-gene interaction., Glucocerebrosidase 1, Parkinson's disease, Zebrafish
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10167297
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