PARK14 patients with homozygous (D331Y) PLA2G6 mutation display motor deficits of pure early-onset Parkinson's disease (PD). The aim of this study is to investigate the pathogenic mechanism of mutant (D331Y) PLA2G6-induced PD. We generated knockin (KI) mouse model of PARK14 harboring homozygous (D331Y) PLA2G6 mutation. Then, we investigated neuropathological and neurological phenotypes of PLA2G6 KI mice and molecular pathogenic mechanisms of (D331Y) PLA2G6-induced degeneration of substantia nigra (SN) dopaminergic neurons. Six-or nine-month-old PLA2G6Y KI mice displayed early-onset cell death of SNpc dopaminergic neurons. Lewy body pathology was found in the SN of PLA2G6 mice. Six-or nine-month-old PLA2G6 KI mice exhibited early-onset parkinsonism phenotypes. Disrupted cristae of mitochondria were found in SNpc dopaminergic neurons of PLA2G6 mice. PLA2G6 mice displayed mitochondrial dysfunction and upregulated ROS production, which may lead to activation of apoptotic cascade. Upregulated protein levels of Grp78, IRE1, PERK, and CHOP, which are involved in activation of ER stress, were found in the SN of PLA2G6 mice. Protein expression of mitophagic proteins, including parkin and BNIP3, was downregulated in the SN of PLA2G6 mice, suggesting that (D331Y) PLA2G6 mutation causes mitophagy dysfunction. In the SN of PLA2G6 mice, mRNA levels of eight genes that are involved in neuroprotection/neurogenesis were decreased, while mRNA levels of two genes that promote apoptotic death were increased. Our results suggest that PARK14 (D331Y) PLA2G6 mutation causes degeneration of SNpc dopaminergic neurons by causing mitochondrial dysfunction, elevated ER stress, mitophagy impairment, and transcriptional abnormality.
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http://dx.doi.org/10.1007/s12035-018-1118-5 | DOI Listing |
Cell Metab
November 2024
Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Penn/CHOP Kidney Innovation Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:
Blood
November 2024
University of Virginia, CHARLOTTESVILLE, Virginia, United States.
Red blood cell (RBC) metabolism regulates hemolysis during aging in vivo and in the blood bank. However, the genetic underpinnings of RBC metabolic heterogeneity and extravascular hemolysis at population scale are incompletely understood. Based on the breeding of 8 founder strains with extreme genetic diversity, the Jackson laboratory diversity outbred population can capture the impact of genetic heterogeneity in like fashion to population-based studies.
View Article and Find Full Text PDFPLoS One
October 2024
Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
Front Immunol
October 2024
Department of Cell, Developmental, and Integrative Biology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
Introduction: We reported that Ca-independent phospholipase Aβ (iPLAβ)-derived lipids (iDLs) contribute to type 1 diabetes (T1D) onset. As CD4 and CD8 T cells are critical in promoting β-cell death, we tested the hypothesis that iDL signaling from these cells participates in T1D development.
Methods: CD4 and CD8 T cells from wild-type non-obese diabetic () and .
J Neuroinflammation
September 2024
National Kunming High-Level Biosafety Primate Research Center, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, 935 Jiaoling Road, Kunming, 650118, Yunnan, China.
Background: During brain aging, disturbances in neuronal phospholipid metabolism result in impaired cognitive function and dysregulation of neurological processes. Mutations in iPLA2β are associated with neurodegenerative conditions that significantly impact brain phospholipids. iPLA2β deficiency exacerbates mitochondrial dysfunction and abnormal mitochondrial accumulation.
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