Unexpected consequences of combined glucocerebrosidase and acid sphingomyelinase deficiency in a model of Parkinson’s disease
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ABSTRACT:
PROVIDER: PRJNA956943 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24207910.fastq.gz | Fastqsanger.gz | |||
| SRR24207911.fastq.gz | Fastqsanger.gz | |||
| SRR24207912.fastq.gz | Fastqsanger.gz | |||
| SRR24207913.fastq.gz | Fastqsanger.gz | |||
| SRR24207914.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description:Advanced age represents one of the major risk factors for Parkinson’s Disease. Recent studies posit a role for microRNAs in Parkinson’s Disease and it is well established that microRNAs are remodelled during ageing, but the relationship between the two processes have not been clarified yet. The aim of the present study is to unravel the relevance of microRNAs as biomarkers of Parkinson’s Disease within the ageing framework. We used Next Generation Sequencing to profile serum microRNAs from samples informative for Parkinson’s Disease (recently diagnosed, drug-naïve Parkinson’s Disease patients) and healthy ageing (centenarians) plus healthy controls age-matched with Parkinson’s Disease patients. Potential candidates, emerging from the combination of differential expression and network analyses, were further validated in an independent cohort including both drug-naïve and advanced Parkinson’s Disease patients together with healthy siblings of Parkinson’s Disease patients at higher genetic risk for Parkinson’s Disease. While we did not find evidences of microRNAs co-regulated in Parkinson’s Disease and ageing, we report that hsa-miR-144-3p is consistently down-regulated in early and advanced Parkinson’s Disease and in Parkinson’s Disease siblings. Interestingly, functional analysis revealed that hsa-miR-144-3p is involved in the regulation of coagulation, a process known to be altered in Parkinson’s Disease. Our results consistently show the down-regulation of hsa-mir144-3p in early and advanced Parkinson’s Disease, robustly confirmed across a variety of analytical and experimental analyses. These results are promising, and additional research is needed to unveil the functional details of its relevance and involvement in Parkinson’s Disease.
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