PUBLICATION
Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency
- Authors
- Keatinge, M., Gegg, M.E., Watson, L., Mortiboys, H., Li, N., Dunning, M., Ailani, D., Bui, H., van Rens, A., Lefeber, D.J., Schapira, A.H.V., MacDonald, R.B., Bandmann, O.
- ID
- ZDB-PUB-230324-41
- Date
- 2023
- Source
- Disease models & mechanisms 16(6): (Journal)
- Registered Authors
- Bandmann, Oliver, Keatinge, Marcus, Li, Nan
- Keywords
- Acid sphingomyelinase, Gene-gene interaction., Glucocerebrosidase 1, Parkinson's disease, Zebrafish
- Datasets
- GEO:GSE229995
- MeSH Terms
-
- Animals
- Glucosylceramidase/genetics
- Glucosylceramidase/metabolism
- Mutation/genetics
- Niemann-Pick Disease, Type A*
- Parkinson Disease*/metabolism
- Phenotype
- Zebrafish/genetics
- Zebrafish/metabolism
- alpha-Synuclein/metabolism
- PubMed
- 36951087 Full text @ Dis. Model. Mech.
Citation
Keatinge, M., Gegg, M.E., Watson, L., Mortiboys, H., Li, N., Dunning, M., Ailani, D., Bui, H., van Rens, A., Lefeber, D.J., Schapira, A.H.V., MacDonald, R.B., Bandmann, O. (2023) Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency. Disease models & mechanisms. 16(6):.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping