Session Information
Date: Tuesday, September 24, 2019
Session Title: Parkinsonisms and Parkinson-Plus
Session Time: 1:45pm-3:15pm
Location: Agora 3 West, Level 3
Objective: To investigate the mechanism of α-synuclein (α-Syn) aggregation.
Background: PLA2G6 has been isolated as the gene responsible for an autosomal recessive form of Parkinson’s disease (PD) linked to the PARK14 locus. PLA2G6 has been proposed to be a key enzyme of phospholipids remodeling through hydrolyze the sn-2 ester bonds of phospholipids. Postmortem studies have shown a marked α-Syn pathology in PARK14 cases. It has been suggested that the alterations of lipid composition affects α-synuclein stability, but the mechanism underlying α-Syn aggregation is insufficiently understood. Here, we used a Drosophila model of PARK14 for investigation of the mechanisms of α-synuclein aggregation through alterations of lipid composition.
Method: We generated Drosophila PLA2G6 (CG6718)–null flies by CRISPR/Cas9 technology and we analyzed the lipid composition in the Drosophila brain by using Electrospray Ionization-Mass Spectrometry. α-Syn was expressed in PLA2G6–null flies and the Drosophila brain was examined by immunohistochemistry, sarkosyl fractionation and real-time quaking-induced conversion (RT-QUIC) to determine whether α-Syn aggregation generated in the brain. We also performed liposome-α-Syn binding assay to estimate the effect of α-Syn stability on phospholipids.
Results: Measurement of brain lipid composition revealed that increased the proportion of phospholipids with short acyl chain in PLA2G6–null flies. PLA2G6–null flies exhibited ubiquitinated α-Syn accumulation in DA neurons as well as other types of neurons. And biochemical assays also revealed the abnormal α-Syn seeding activity. The liposome assay showed that the interaction between α-Syn and lipids were modulated by the length of acyl chain.
Conclusion: Our fly models suggest that changes in the acyl-chain composition of phospholipids are critical for α-Syn aggregation. We proposed that the dietary manipulation of lipids is a promising method to control risks for PD.
To cite this abstract in AMA style:
ａ. Mori, T. Hatano, T. Inoshita, K. Shiba-Fukushima, T. Koinuma, C. Yamashita, A. Okuzumi, Y. Imai, ｎ. Hattori. Parkinson’s disease-associated mutations of PLA2G6 alters the membrane dynamics and α-synuclein stability [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/parkinsons-disease-associated-mutations-of-pla2g6-alters-the-membrane-dynamics-and-%ce%b1-synuclein-stability/. Accessed November 21, 2024.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsons-disease-associated-mutations-of-pla2g6-alters-the-membrane-dynamics-and-%ce%b1-synuclein-stability/