Rare genetic variation in mitochondrial pathways influences the risk for Parkinson's disease

Gaare, Johannes Jernqvist; Nido, Gonzalo S.; Sztromwasser, Paweł; Knappskog, Per M.; Dahl, Olav; Lund‐Johansen, Morten; Maple‐Grødem, Jodi; Alves, Guido; Tysnes, Ole‐Bjørn; Johansson, Stefan; Haugarvoll, Kristoffer; Tzoulis, Charalampos

doi:10.1002/mds.64

Cited by 53 publications

(52 citation statements)

References 45 publications

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“…5,6,9 Such combined analyses are also useful for analysis of associations with phenotypes or biomarkers, 28,29 and currently burden analyses of multiple genes from the same pathways are routinely performed. 16,30 Such recent analysis demonstrated that there is a burden of lysosomal storage disease-causing genes in PD, which was mainly driven by GBA but also by SMPD1, 16 further supporting the current results.…”

Section: Discussionsupporting

confidence: 87%

SMPD1 mutations, activity, and α‐synuclein accumulation in Parkinson's disease

et al. 2019

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Background SMPD1 (acid‐sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD. Methods SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid‐sphingomyelinase activity was measured by a mass spectrometry‐based assay in the New York cohort. α‐Synuclein levels were measured in vitro following CRISPR/Cas9‐mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)‐M17 cells. Lysosomal localization of acid‐sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid‐sphingomyelinase structure was performed. Results SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6‐8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid‐sphingomyelinase activity was associated with a 3.5‐ to 5.8‐year earlier onset of PD in the lowest quartile versus the highest quartile of acid‐sphingomyelinase activity (P = 0.01‐0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α‐synuclein levels in HeLa and BE(2)‐M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid‐sphingomyelinase to the lysosome. Conclusions Our results support an association between SMPD1 variants, acid‐sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid‐sphingomyelinase activity may lead to α‐synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society

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Section: Discussionsupporting

confidence: 87%

SMPD1 mutations, activity, and α‐synuclein accumulation in Parkinson's disease

et al. 2019

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“…Interestingly, biallelic mutations in MRPS34 are known to cause a form of Leigh syndrome, characterised by neurodegeneration in infancy with dystonia and choreoathetoid movements due to basal ganglia dysfunction. Furthermore, we note that a recent study that utilized whole exome sequencing (WES) data from two PD cohorts to investigate rare variation in nuclear genes associated with distinct mitochondrial processes, not only provided support for the involvement of mitochondrial function in sporadic PD, but also identified the gene, MRPL43, which encodes a component of the large mitochondrial ribosomal subunit 34 . Interestingly, MRPL43 and MRPS34 were amongst five genes which were also highly co-expressed in human brain with genes already known to cause monogenic forms of PD.…”

Section: Discussionmentioning

confidence: 83%

Genetic variation within genes associated with mitochondrial function is significantly associated with later age at onset of Parkinson disease and contributes to disease risk

Billingsley

Barbosa

Bandrés‐Ciga

et al. 2018

Preprint

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Mitochondrial dysfunction has been implicated in the aetiology of monogenic Parkinson's disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here we comprehensively assessed the role of mitochondrial function associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. First, we identified that a proportion of the "missing heritability" of the PD can be explained by common variation within genes implicated in mitochondrial disease (primary gene list) and mitochondrial function (secondary gene list). Next we calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. Most significantly we further report that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomisation, which showed that 14 of these mitochondrial function associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD.

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“…The first cohort (n = 29) comprised individuals with idiopathic PD (n = 18) from the Park-West study (PW), a prospective population-based cohort which has been described in detail [38] and neurologically healthy controls (Ctrl, n = 11) from our brain bank for aging and neurodegeneration. Whole-exome sequencing had been performed on all patients [39] and known/predicted pathogenic mutations in genes implicated in Mendelian PD and other monogenic neurological disorders had been excluded. None of the study participants had clinical signs of mitochondrial disease or use of medication known to influence mitochondrial function ( Supplementary File 1).…”

Section: Subject Cohortsmentioning

confidence: 99%

Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition

Nido

Dick

Toker

et al. 2019

Preprint

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AbstractBackgroundThe etiology of Parkinson’s disease (PD) is largely unknown. Genome-wide transcriptomic studies in bulk brain tissue have identified several molecular signatures associated with the disease. While these studies have the potential to shed light into the pathogenesis of PD, they are also limited by two major confounders: RNA post mortem degradation and heterogeneous cell type composition of bulk tissue samples. We performed RNA sequencing following ribosomal RNA depletion in the prefrontal cortex of 49 individuals from two independent case-control cohorts. Using cell-type specific markers, we estimated the cell-type composition for each sample and included this in our analysis models to compensate for the variation in cell-type proportions.ResultsRibosomal RNA depletion results in substantially more even transcript coverage, compared to poly(A) capture, in post mortem tissue. Moreover, we show that cell-type composition is a major confounder of differential gene expression analysis in the PD brain. Correcting for cell-type proportions attenuates numerous transcriptomic signatures that have been previously associated with PD, including vesicle trafficking, synaptic transmission, immune and mitochondrial function. Conversely, pathways related to endoplasmic reticulum, lipid oxidation and unfolded protein response are strengthened and surface as the top differential gene expression signatures in the PD prefrontal cortex.ConclusionsDifferential gene expression signatures in PD bulk brain tissue are significantly confounded by underlying differences in cell-type composition. Modeling cell-type heterogeneity is crucial in order to unveil transcriptomic signatures that represent regulatory changes in the PD brain and are, therefore, more likely to be associated with underlying disease mechanisms.

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Rare genetic variation in mitochondrial pathways influences the risk for Parkinson's disease

Cited by 53 publications

References 45 publications

SMPD1 mutations, activity, and α‐synuclein accumulation in Parkinson's disease

SMPD1 mutations, activity, and α‐synuclein accumulation in Parkinson's disease

Genetic variation within genes associated with mitochondrial function is significantly associated with later age at onset of Parkinson disease and contributes to disease risk

Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition

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