Imperial College London
Alternate

DrHelenaCocheme

Faculty of Medicine, Institute of Clinical Sciences

Honorary Senior Lecturer
 
 
 
//

Contact

 

helena.cocheme Website

 
 
//

Location

 

4.15ELMS BuildingHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Kinghorn:2015:brain/awv132,
author = {Kinghorn, KJ and Castillo-Quan, JI and Bartolome, F and Angelova, PR and Li, L and Pope, S and Cochemé, HM and Khan, S and Asghari, S and Bhatia, KP and Hardy, J and Abramov, AY and Partridge, L},
doi = {brain/awv132},
journal = {Brain},
pages = {1801--1816},
title = {Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction},
url = {http://dx.doi.org/10.1093/brain/awv132},
volume = {138},
year = {2015}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta enzyme that selectively hydrolyses glycerophospholipids to release free fatty acids. Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. More recently, PLA2G6 was identified as the causative gene in a subgroup of patients with autosomal recessive early-onset dystonia-parkinsonism. Neuropathological examination revealed widespread Lewy body pathology and the accumulation of hyperphosphorylated tau, supporting a link between PLA2G6 mutations and parkinsonian disorders. Here we show that knockout of the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in reduced survival, locomotor deficits and organismal hypersensitivity to oxidative stress. Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology. Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels. We confirmed our findings using cultured fibroblasts taken from two patients with mutations in the PLA2G6 gene. Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species. Finally, we demonstrated that deuterated polyunsaturated fatty acids, which inhibit lipid peroxidation, were able to partially rescue the locomotor abnormalities seen in aged flies lacking iPLA2-VIA gene function, and restore mitochondrial membrane potential in fibroblasts from patients with PLA2G6 mutations. Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalit
AU  - Kinghorn,KJ
AU  - Castillo-Quan,JI
AU  - Bartolome,F
AU  - Angelova,PR
AU  - Li,L
AU  - Pope,S
AU  - Cochemé,HM
AU  - Khan,S
AU  - Asghari,S
AU  - Bhatia,KP
AU  - Hardy,J
AU  - Abramov,AY
AU  - Partridge,L
DO  - brain/awv132
EP  - 1816
PY  - 2015///
SN  - 1460-2156
SP  - 1801
TI  - Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction
T2  - Brain
UR  - http://dx.doi.org/10.1093/brain/awv132
UR  - http://hdl.handle.net/10044/1/31382
VL  - 138
ER  -
Download