Loss of acid sphingomyelinase ameliorates disease progression in a vertebrate model of Glucocerebrosidase deficiency
Keatinge, M.; Gegg, M.; Watson, L.; Mortiboys, H.; Bui, H.; van Leens, A.; Lefeber, D.; MacDonald, R.; Schapira, A.; Bandmann, O.
Show abstract
The additive effect of genetic risk variants on overall disease risk is a plausible but frequently unproven hypothesis. To test this hypothesis, we assessed the biological effect of combined glucocerebrosidase (GCase) and acid sphingomyelinase (ASM) deficiency. Variants in both glucocerebrosidase1 (GBA1) and sphingomyelinase (SMPD1) are genetic risk factors for Parkinsons disease. Unexpectedly, ASM deficiency resulted in normalized behaviour and prolonged survival in gba1-/-;smpd1-/- double-mutant zebrafish compared to gba1-/-. RNAseq-based pathway analysis confirmed a profound rescue of neuronal function and intracellular homeostasis. We identified complete reciprocal rescue of mitochondrial respiratory chain function and abolished lipid membrane oxidation in gba1-/-;smpd1-/- compared to gba1-/- or smpd1-/- as the underlying rescue mechanism. Complementing in vitro experiments demonstrated an unexpected reduction of -synuclein levels in human cell lines with combined GCase and ASM deficiency. Our study highlights the importance of functional validation for any putative interactions between genetic risk factors and their overall effect on disease-relevant mechanisms rather than readily assuming an additive effect. SummaryThe additive effect of genetic risk variants on disease risk is a popular but typically unproven hypothesis. We investigated this hypothesis mechanistically for Parkinsons disease risk factors and provide evidence of an unexpected rescue effect on neuronal function and survival.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants 94%
- Sequential screening nominates the Parkinson's disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis 94%
- Ataxia Telangiectasia patient-derived neuronal and brain organoid models reveal mitochondrial dysfunction and oxidative stress 94%
Similar papers in this journal
- The GBA variant E326K is associated with alpha-synuclein aggregation and lipid droplet accumulation in human cell lines. 95%
- Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria 93%
- Mouse models of NADK2 deficiency analyzed for metabolic and gene expression changes to elucidate pathophysiology 93%
Similar papers in this journal
- Loss of a subunit of vacuolar ATPase identifies unexpected biological signatures of reduced organelle acidification in vivo 94%
- Loss Of lrrk2 Impairs Cell Proliferation And Neuronal Regeneration In The Zebrafish Brain 94%
- Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.