Four novel rare mutations of PLA2G6 in Chinese population with Parkinson's disease

Gui, Yaxing; Xu, Zhongping; Wen-Lv,; Liu, Hongmei; Zhao, Jin-Jia; Hu, Xingyue

doi:10.1016/j.parkreldis.2012.07.016

Cited by 49 publications

(59 citation statements)

References 29 publications

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“…(Meng, et al, 2012) However, one of the GWAS loci that was identified in melanoma(Meng, et al, 2012) and melanocytic cutaneous nevi(Falchi, et al, 2009) cohorts is the PLA2G6 locus. Interestingly, mutations in PLA2G6 may cause PD or Parkinsonism-dystonia syndrome,(Gui, et al, 2013,Kauther, et al, 2011,Malaguti, et al, 2015,Paisan-Ruiz, et al, 2009) suggesting a potential genetic link between the two conditions. (Paisan-Ruiz and Houlden, 2010) Another intriguing locus that was identified in PD GWAS is around the GPNMB gene,(Nalls, et al, 2014) which codes for the glycoprotein non-metastatic melanoma protein B, which may have an important role in melanoma.…”

Section: Discussionmentioning

confidence: 99%

The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder

Gan‐Or

Mohsin

Girard

et al. 2016

Neurobiology of Aging

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The MC1R gene, suggested to be involved in Parkinson disease (PD) and melanoma, was sequenced in PD patients (n=539) and controls (n=265) from New-York, and PD patients (n=551), rapid eye movement sleep behavior disorder (RBD) patients (n=351) and controls (n=956) of European ancestry. Sixty-eight MC1R variants were identified, including 7 common variants with frequency>0.01. None of the common variants was associated with PD or RBD in the different regression models. In a meta-analysis with fixed-effect model, the p.R160W variant was associated with an increased risk for PD (OR=1.22, 95%CI 1.02-1.47, p=0.03) but with significant heterogeneity (p=0.048). Removing one study that introduced the heterogeneity resulted in non-significant association (OR=1.11, 95%CI 0.92-1.35, p=0.27, heterogeneity p=0.57). Rare variants had similar frequencies in patients and controls (10.54% and 10.15%, respectively, p=0.75), and no cumulative effect of carrying more than one MC1R variant was found. The current study does not support a role for the MC1R p.R160W and other variants in susceptibility for PD or RBD.

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Section: Discussionmentioning

confidence: 99%

The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder

Gan‐Or

Mohsin

Girard

et al. 2016

Neurobiology of Aging

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“…Homozygosity mapping and mutational analyses over the past 5 years reveals a complicated connection with mutations in the PLA2G6 gene at the PARK14 locus. Initially recognized in adult-onset parkinsonism ( 316 ), PLA2G6 gene mutations are now linked to levodopa-responsive parkinsonism with severe impairments in swallowing, dystonia, and pyramidal weakness ( 317,318 ), and to autosomal early-onset parkinsonism ( 313,(318)(319)(320)(321)(322). However, studies among Asian populations are confl icting, where a link between PLA2G6 mutations and Parkinson's disease was reported in Singapore ( 323 ), but not in China ( 324,325 ) or Japan ( 326 ).…”

Section: Ipla 2 ␤ and Diseasesmentioning

confidence: 99%

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

169

190

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The Ca 2+ -independent phospholipases A 2 (iPLA 2 s) are part of a diverse family of PLA 2 s that hydrolyze the sn -2 substituent from membrane phospholipids to release a free fatty acid and a lysolipid ( 1, 2 ). These enzymes are ubiquitously expressed, and in contrast to secretory PLA 2 s (sPLA 2 s) and cytosolic PLA 2 s (cPLA 2 s), do not require Ca 2+ for either translocation or activity. Some of the fi rst descriptions of iPLA 2 activity were in the mid-to late-1980s with the identifi cation of a plasmalogen-selective PLA 2 in Abstract Among the family of phospholipases A 2 (PLA 2 s) are the Ca 2+ -independent PLA 2 s (iPLA 2 s) and they are designated group VI iPLA 2 s. In relation to secretory and cytosolic PLA 2 s, the iPLA 2 s are more recently described and details of their expression and roles in biological functions are rapidly emerging. The iPLA 2 s or patatin-like phospholipases (PNPLAs) are intracellular enzymes that do not require Ca 2+ for activity, and contain lipase (GXSXG) and nucleotide-binding (GXGXXG) consensus sequences. Though nine PNPLAs have been recognized, PNPLA8 (membraneassociated iPLA 2 ␥ ) and PNPLA9 (cytosol-associated iPLA 2 ␤ ) are the most widely studied and understood. The iPLA 2 s manifest a variety of activities in addition to phospholipase, are ubiquitously expressed, and participate in a multitude of biological processes, including fat catabolism, cell differentiation, maintenance of mitochondrial integrity, phospholipid remodeling, cell proliferation, signal transduction, and cell death. As might be expected, increased or decreased expression of iPLA 2 s can have profound effects on the metabolic state, CNS function, cardiovascular performance, and cell survival; therefore, dysregulation of iPLA 2 s can be a critical factor in the development of many diseases. This review is aimed at providing a general framework of the current understanding of the iPLA 2 s and discussion of the potential mechanisms of action of the iPLA 2 s and related involved lipid mediators. -Ramanadham, S

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“…It has been proposed that α-syn can interact with FA, oxidized lipids, and LD [16–18]. However, little is known about the mechanisms of FA turnover and lipid remodeling that operate during oxidative stress injury in dopaminergic neurons.…”

Section: Introductionmentioning

confidence: 99%

Dopaminergic Neurons Respond to Iron-Induced Oxidative Stress by Modulating Lipid Acylation and Deacylation Cycles

et al. 2015

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Metal-imbalance has been reported as a contributor factor for the degeneration of dopaminergic neurons in Parkinson Disease (PD). Specifically, iron (Fe)-overload and copper (Cu) mis-compartmentalization have been reported to be involved in the injury of dopaminergic neurons in this pathology. The aim of this work was to characterize the mechanisms of membrane repair by studying lipid acylation and deacylation reactions and their role in oxidative injury in N27 dopaminergic neurons exposed to Fe-overload and Cu-supplementation. N27 dopaminergic neurons incubated with Fe (1mM) for 24 hs displayed increased levels of reactive oxygen species (ROS), lipid peroxidation and elevated plasma membrane permeability. Cu-supplemented neurons (10, 50 μM) showed no evidence of oxidative stress markers. A different lipid acylation profile was observed in N27 neurons pre-labeled with [3H] arachidonic acid (AA) or [3H] oleic acid (OA). In Fe-exposed neurons, AA uptake was increased in triacylglycerols (TAG) whereas its incorporation into the phospholipid (PL) fraction was diminished. TAG content was 40% higher in Fe-exposed neurons than in controls. This increase was accompanied by the appearance of Nile red positive lipid bodies. Contrariwise, OA incorporation increased in the PL fractions and showed no changes in TAG. Lipid acylation profile in Cu-supplemented neurons showed AA accumulation into phosphatidylserine and no changes in TAG. The inhibition of deacylation/acylation reactions prompted an increase in oxidative stress markers and mitochondrial dysfunction in Fe-overloaded neurons. These findings provide evidence about the participation of lipid acylation mechanisms against Fe-induced oxidative injury and postulate that dopaminergic neurons cleverly preserve AA in TAG in response to oxidative stress.

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Four novel rare mutations of PLA2G6 in Chinese population with Parkinson's disease

Cited by 49 publications

References 29 publications

The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder

The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Dopaminergic Neurons Respond to Iron-Induced Oxidative Stress by Modulating Lipid Acylation and Deacylation Cycles

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